Matrix metalloproteinase inhibitors

ABSTRACT

The present invention relates to β-hydroxy and amino-substituted carboxylic acids, which act as matrix metalloproteinase inhibitors, particularly diastereomerically pure β-hydroxy carboxylic acids, corresponding processes for their synthesis, and pharmaceutical compositions containing the compounds of the present invention. Compounds of the present invention are useful in the treatment of various inflammatory, autoimmune, and allergic diseases, such as methods of treating asthma, rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriatic arthritis, psoriasis, pulmonary fibrosis, wound healing disorders, pulmonary inflammation, acute respiratory distress syndrome, perodontitis, multiple sclerosis, gingivitis, atherosclerosis, neointimal proliferation, which leads to restenosis and ischemic heart failure, stroke, renal diseases, tumor metastasis, and other inflammatory disorders characterized by the over-expression and over-activation of a matrix metalloproteinase.

FIELD OF THE INVENTION

The present invention relates to certain β-hydroxy- andamino-substituted carboxylic acids as matrix metalloproteinaseinhibitors, particularly diastereomerically pure β-hydroxy-carboxylicacids, and to processes for their syntheses.

This invention also relates to pharmacological compositions containingthe compounds of the present invention, and methods of treating asthma,rheumatoid arthritis, COPD, rhinitis, osteoarthritis, psoriaticarthritis, psoriasis, pulmonary fibrosis, wound healing disorders,pulmonary inflammation, acute respiratory distress syndrome,perodontitis, multiple sclerosis, gingivitis, atherosclerosis,neointimal proliferation which leads to restenosis and ischemic heartfailure, stroke, renal diseases, tumor metastasis, and otherinflammatory disorders characterized by the over-expression andover-activation of a matrix metalloproteinase by using said compounds.

BACKGROUND OF THE INVENTION

Matrix metalloproteinases (MMPs) are a naturally occurring superfamilyof proteinases (enzymes) found in most mammals. The superfamily iscomposed of at least 26 members of zinc-containing enzymes produced bymany cell types and sharing structural and functional features. Based onstructural and functional considerations proteinases have beenclassified into different families and subfamilies (Vartak et al., J.Drug Targeting, 15, 1-20 (2007) and Hooper, FEBS Letters, 354, 1-6(1994)), such as collagenases (MMP-1, -8, and -13), gelatinases (MMP-2and -9), metalloelastases (MMP-12), the MT-MMPs (MMP-14, -15, -16, -17,-24, and -25), matrilysins (MMP-7 and -26), stromelysins (MMP-3, -10,and -11) and sheddases such as TNF-converting enzymes (TACE and ACE).

Metalloproteinases are believed to be important in physiological diseaseprocesses that involve remodeling such as embryonic development, boneformation, and uterine remodeling during menstruation. One majorbiological function of MMPs is to catalyze the breakdown of connectivetissues or extra-cellular matrix by their ability to hydrolyze variouscomponents of tissue or matrix. Apart from their role in degradingconnective tissue, MMPs are involved in the activation of zymogen (pro)forms of other MMPs, thereby inducing MMP activation. They are alsoinvolved in the biosynthesis of TNF-alpha which is implicated in manypathological conditions.

MMP-12, also known as macrophage elastase or metalloelastase, isexpressed in activated macrophages and has been shown to be secretedfrom alveolar macrophages from smokers as well as in foam cells inatherosclerotic lesions. MMP-12 knockout mouse studies have shown thedevelopment of significant emphysema, thus supporting its role in COPD.MMP-9 (gelatinase B, 92 kDa type IV collagenase) is one member of theMMP family that is released as a proenzyme and subsequently activatedvia a protease cascade in vivo.

The concentration of MMP-9 is increased in diseases like asthma,interstitial pulmonary fibrosis (IPF), adult respiratory distresssyndrome (ARDS), and chronic obstructive pulmonary disease (COPD).Because of its proteolytic ability, MMP-9 has been implicated in tissueremodelling of the airways and lungs in chronic inflammatory diseasessuch as severe asthma and COPD. MMP-9 is also likely to bephysiologically important because of its ability to regulate thedigestion of components of the extracellular matrix as well as theactivity of other proteases and cytokines MMP-9 is secreted inneutrophils, macrophages, and osteoclasts, which are easily induced bycytokines and growth factors, and plays a role in various physiologicaland pathological processes.

Over-expression or over-activation of an MMP or an imbalance between anMMP and a natural (i.e., endogenous) tissue inhibitor of a matrixmetalloproteinase (TIMP) has been linked to a pathogenesis of diseasescharacterized by the breakdown of connective tissue or extracellularmatrix.

Inhibition of the activity of one or more MMPs may be of benefit in thetreatment of various inflammatory, autoimmune and allergic diseases suchas inflammation of the joint, inflammation of the GI tract, inflammationof the skin, collagen remodeling, wound healing disorders, etc.

The design and therapeutic application of MMP inhibitors has revealedthat the requirement of a molecule to be an effective inhibitor of MMPclass of enzymes is a functional group (e.g., carboxylic acid,hydroxamic acid, or sulphydryl) capable of chelating to the active siteZn²⁺ ion (Whittaker et al., Chem. Rev., 99, 2735-76, (1999)).

WO 2004/110974 discloses compounds and their physiologically functionalderivatives described as inhibitors of matrix metalloproteinase enzymes.WO 2004/113279 discloses alleged inhibitors of matrix metalloproteinase.WO 2005/026120 discloses compounds also described as inhibitors ofmatrix metalloproteinase. U.S. Pat. No. 6,350,885 discloses tricyclicheteroaromatic compounds and their derivatives believed to be inhibitorsof matrix metalloproteinases. WO 98/09940 discloses biphenyl butyricacids and their derivatives described as inhibitors of matrixmetalloproteinases. J. Med. Chem., Vol. 11(6), 1139-1144 (1968),discloses the synthesis and anti-inflammatory activity of4-(p-biphenylyl)-3-hydroxybutyric acid and related compounds. WO96/15096 discloses substituted 4-biarylbutyric or 5-biarylpentanoicacids and derivatives as alleged matrix metalloproteinase inhibitors. WO2006/090235 describes 5-phenyl-pentanoic acid derivatives described asmatrix metalloproteinase inhibitors for the treatment of asthma andother diseases.

Research has been carried out into the identification of inhibitors thatare selective, e.g., for a few of the MMP subtypes. An MMP inhibitor ofimproved selectivity would avoid potential side effects associated withinhibition of MMPs that are not involved in the pathogenesis of thedisease being treated.

Further, the use of more selective MMP inhibitors would requireadministration of a lower amount of the inhibitor for treatment of thedisease than would otherwise be required and, after administration,partitioned in vivo among multiple MMPs. Still further, theadministration of a lower amount of the compound would improve themargin of safety between the dose of the inhibitor required fortherapeutic activity and the dose of the inhibitor at which toxicity isobserved.

Many drugs exist as asymmetric three-dimensional molecules, i.e.,chiral, and will therefore have several stereoisomers, depending uponthe number of chiral centers present. The importance of evaluating newchemical entities having chiral centers as single isomers is tounderstand their effect on pharmacological and toxicological aspects.There are often pharmacodynamic, pharmacokinetic, and/or toxicologicaldifferences between enantiomers/diastereomers. Even if naturalphysiological mediators are achiral, based on their target environment,their receptors/enzymes may demonstrate a preference for only oneoptically pure enantiomer of agonists, antagonists, or inhibitors. Froma pharmacokinetics point of view, chirality can have an influence ondrug absorption, distribution, metabolism, and elimination. Pure singleisomers may also offer advantages in terms of these pharmacokineticparameters, thus enabling better developability of such molecules asdrug candidates. It is also known that chirality has a significanteffect of the physicochemical properties and crystallinity of a chiralmolecule, which in turn have profound effects on the pharmacokineticsand developability of the molecule. Besides those mentioned above,regulatory principles guide one to preferably develop single isomers asdrug candidates in order to avoid any pharmacological, pharmacokinetic,and toxicological problems that may arise due to interactions of anunwanted isomer with undesirable molecular targets.

In this context, synthetic strategies to produce pure single isomersoffer advantages over analytical techniques of separation of isomers,not only in terms of cost and efficiency but larger amounts of compoundcan be prepared for elaborate pharmaceutical testing. Thus, compounds ofpresent invention, which are single chiral isomers, have improvedpotency, improved pharmacokinetics, and/or improved physicochemicalproperties as compared to racemic compounds.

The present invention is directed to overcoming problems encountered inthe art.

SUMMARY OF THE INVENTION

The present invention relates to β-hydroxy and amino substitutedcarboxylic acids, which act as matrix metalloproteinase inhibitors,particularly diastereomerically pure β-hydroxy carboxylic acids,corresponding processes for the synthesis of and pharmaceuticalcompositions containing the compounds of the present invention. Thepresent invention relates to matrix metalloproteinase inhibitors usefulas effective therapeutic or prophylactic agents in treatment of variousinflammatory, autoimmune, and allergic diseases and other inflammatorydisorders characterized by the over-expression and over-activation of amatrix metalloproteinase using the compounds.

The present invention relates to compounds that act as dual MMP-9/12inhibitors, which have desirable activity profiles and beneficialpotency, selectivity, and/or pharmacokinetic properties.

The present invention includes new chemical entities having chiralcenters as single isomers. Synthetic strategies to produce pure singleisomers that offer advantages over analytical techniques of separationof isomers, not only in terms of cost and efficiency, but also a largeramount of the compound can be prepared for elaborate pharmaceuticaltesting are also provided.

Other aspects will be set forth in the description which follows, and inpart will be apparent from the description or may be learned by thepractice of the invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compounds having the structure ofFormula I:

wherein

-   -   * denotes or represents a stereogenic or asymmetric center of        defined configuration selected from (R,R), (S,S), (R,S), and        (S,R);    -   n is an integer from 1 to 5;    -   R₁ is hydrogen, optionally substituted alkyl, alkenyl, alkynyl,        cycloalkyl, aryl, heterocyclyl, heteroaryl, aralkyl, alkoxy,        aryloxy, alkenyloxy or alkynyloxy; and    -   R₂ is heterocyclyl, heteroaryl, NR₄R₅, —NHC(═Y)R₄,        —NHC(═Y)NR₅R_(x), —NHC(═O)OR₄, —NHSO₂R₄, C(═Y)NR₄R₅, or        C(═O)OR₆;        wherein    -   Y is oxygen, sulphur, OR₅, —OC(═O)NR₄R₅, O-acyl, S(O)_(m)R₄,        —SO₂N(R₄)₂, cyano, amidino, or guanidine;    -   R_(x) is R₄ or —SO₂N(R₄)₂; and    -   R₆ is hydrogen, alkyl, cycloalkyl, aralkyl, heteroarylalkyl,        heterocyclylalkyl, or cycloalkylalkyl;        wherein    -   R₄ is alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heterocyclyl,        heteroaryl, aralkyl, heteroarylalkyl, heterocyclylalkyl, or        cycloalkylalkyl;    -   m is an integer from 0 to 2;    -   R₅ is hydrogen or R₄;    -   R₃ is hydrogen, fluorine, alkyl, cycloalkylalkyl, or aralkyl;    -   A is OH, OR₄, —OC(═O)NR₄R₅, O-acyl, NH₂, NR₄R₅, —NHC(═Y)R₄,        —NHC(═Y)NR₅R_(x), —NHC(═O)OR₄, or —NHSO₂R₄; and    -   Q is optionally substituted aryl or heteroaryl.

Compounds of Formula I have particularly advantageous properties, whichmay include biological activities, such as modelling of LPS-included ratneutrophilia, selective inhibition of MMP-9 and MMP-12 activity, andinhibition of these activities without selectivity towards MMP-1activity. Further, these advantageous properties may includesolubilities which enhance preparation and administration of dosageforms, and improved bioavailability, as compared to known compounds, forexample, those of WO 2005/026120.

In one embodiment, the invention relates to compounds of general FormulaIa,

wherein

-   -   * denotes or represents a stereogenic or asymmetric center of        defined configuration selected from (R,R), (S,S), (R,S), and        (S,R);    -   p is an integer from 1 to 3;    -   R_(1a) is an optionally substituted aryl or heteroaryl;    -   R_(2a) is a 5-6 membered N-containing heterocyclyl linked        through N atom, which is optionally fused to aryl or heteroaryl,        or spirofused to cycloalkyl, which can optionally be further        substituted with one or more oxo groups, alkyl, cycloalkyl,        halo, alkoxy, trifluoroalkyl, or aryl; and    -   Q_(a) is an optionally substituted 5 or 6 membered heteroaryl        containing 1 to 3 heteroatoms selected from O, N, or S.

Compounds of Formula Ia have particularly advantageous properties, whichmay include biological activities, such as modelling of LPS-included ratneutrophilia, selective inhibition of MMP-9 and MMP-12 activity, andinhibition of these activities without selectivity towards MMP-1activity. Further, these advantageous properties may includesolubilities which enhance preparation and administration of dosageforms, and improved bioavailability, as compared to known compounds, forexample, those of WO 2005/026120.

In another embodiment, the invention relates to compounds of generalFormula Ib,

wherein

-   -   * denotes or represents a stereogenic or asymmetric center of        defined configuration selected from (R,R), (S,S), (R,S), and        (S,R);    -   p is an integer from 1 to 3;    -   R_(1b) is an optionally substituted phenyl or heteroaryl wherein        optional substituents can be selected from one or more of alkyl,        cycloalkyl, halo, alkoxy, trifluoroalkyl, or aryl; and    -   R_(2b) is a 5-6 membered N-containing heterocyclyl linked        through N atom, which is optionally fused to aryl or heteroaryl,        or spirofused to cycloalkyl, which can optionally be further        substituted with one or more oxo group, alkyl, cycloalkyl, halo,        alkoxy, trifluoroalkyl, or aryl.

Compounds of Formula Ib have particularly advantageous properties, whichmay include biological activities, such as modelling of LPS-included ratneutrophilia, selective inhibition of MMP-9 and MMP-12 activity, andinhibition of these activities without selectivity towards MMP-1activity. Further, these advantageous properties may includesolubilities which enhance preparation and administration of dosageforms, and improved bioavailability, as compared to known compounds, forexample, those of WO 2005/026120.

In another embodiment, the invention relates to compounds of generalFormula Ic,

wherein

-   -   * denotes or represents a stereogenic or asymmetric center of        defined configuration selected from (R,R), (S,S), (R,S), and        (S,R);    -   p is an integer from 1 to 3;    -   R_(1c) is optionally substituted phenyl, pyridyl, pyrimidyl,        thienyl, or pyrazolyl; wherein optional substitutent can be        selected from with one or more alkyl, halo, alkoxy,        trifluoroalkyl, or aryl; and    -   R_(2c) is a 5-6 membered N-containing heterocyclyl linked        through N atom, which is optionally fused to aryl or heteroaryl,        or spirofused to cycloalkyl, which can optionally be further        substituted with one or more oxo group, alkyl, cycloalkyl, halo,        alkoxy, trifluoroalkyl, or aryl.

In compounds of Formula Ic, R_(2c) represents 5-6 membered N-containingheterocyclyl linked through N atom, which is optionally fused to aryl orheteroaryl, or spirofused to cycloalkyl, for example, benzotriazinone,isoindoledione, pyrimidinedione, aza-spiro[4.5]decanedione,benzo-oxazinedione, imidazolidinedione, or phthalazinone.

Compounds of Formula Ic have particularly advantageous properties, whichmay include biological activities, such as modelling of LPS-included ratneutrophilia, selective inhibition of MMP-9 and MMP-12 activity, andinhibition of these activities without selectivity towards MMP-1activity. Further, these advantageous properties may includesolubilities which enhance preparation and administration of dosageforms, and improved bioavailability, as compared to known compounds, forexample, those of WO 2005/026120.

The diastereomers, rotational isomers, N-oxides, polymorphs,pharmaceutically acceptable salts and pharmaceutically acceptablesolvates of these compounds, prodrugs, and metabolites having the sametype of activity are also provided, as well as pharmaceuticalcompositions comprising the compounds, their metabolites, diastereomers,conformational isomers, N-oxides, polymorphs, solvates, orpharmaceutically acceptable salts thereof, in combination with apharmaceutically acceptable carrier and optionally included excipients.

In one embodiment, the invention encompasses compounds of Formula (I),which may include, but are not limited to, the following, for example,

-   (2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoic    acid (Compound No. 1);-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 2);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 3);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 4);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 5);-   (2S,3R)-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 6);-   (2S,3R)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 7);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 8);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 9);-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 10);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 11);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 12);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 13);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 14);-   (2S,3R)-5-(4′-chloro-3′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 15);-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 16);-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 17);-   (2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 18);-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 19);-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-chlorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 20);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 21);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 22);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 23);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 24);-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 25);-   (2S,3R)-5-(4′-ethylbiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 26);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 27);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 28);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-pyrimidin-5-ylphenyl)pentanoic    acid (Compound No. 29);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 30);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-pyridin-3-ylphenyl)pentanoic    acid (Compound No. 31);-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 32);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 33);-   (2S,3R)-3-hydroxy-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 34);-   (2S,3R)-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 35);-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 36);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 37);-   (2S,3R)-3-hydroxy-2-{2-[7-(6-methoxypyridin-3-yl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl]ethyl}-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 38);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 39);-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 40);-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 41);-   (2S,3R)-3-hydroxy-2-{2-[5-(6-methoxypyridin-3-yl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl]ethyl}-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 42);-   (2S,3R)-5-(4′-chloro-3′-fluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 43);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 44);-   (2S,3R)-5-biphenyl-4-yl-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 45);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 46);-   (2S,3R)-5-(3,3′-difluoro-4′-methoxybiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 47);-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 48);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(1H-tetrazol-1-yl)phenyl]pentanoic    acid (Compound No. 49);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 50);-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 51);-   (2S,3R)-3-hydroxy-5-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 52);-   (2S,3R)-5-biphenyl-4-yl-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 53);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 54);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl]-3-hydroxypentanoic    acid (Compound No. 55);-   (2S,3R)-5-(4′-chloro-3-fluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 56);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[6-(4-methoxyphenyl)pyridin-3-yl]pentanoic    acid (Compound No. 57);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 58);-   (2S,3R)-5-[6-(4-chlorophenyl)pyridin-3-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 59);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 60);-   (2S,3R)-5-[4-(4-chlorophenyl)-2-thienyl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 61);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)-2-thienyl]pentanoic    acid (Compound No. 62);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-{4-[4-(trifluoromethyl)phenyl]-2-thienyl}pentanoic    acid (Compound No. 63);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[4-(3-fluoro-4-methoxyphenyl)-2-thienyl]-3-hydroxypentanoic    acid (Compound No. 64);-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 65);-   (2S,3R)-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 66);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 67);-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 68);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 69);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[2-fluoro-5-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 70);-   (2S,3R)-5-(4′-chloro-4-fluorobiphenyl-3-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 71);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-fluoro-4′-(trifluoromethyl)biphenyl-3-yl]-3-hydroxypentanoic    acid (Compound No. 72);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[4-fluoro-3-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 73);-   (2S,3R)-5-(4′-chloro-6-fluorobiphenyl-3-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 74);-   (2S,3R)-5-(3′,6-difluoro-4′-methoxybiphenyl-3-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 75);-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 76);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 77);-   (2S,3R)-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 78);-   (2S,3R)-2-[2-(5-chloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 79);-   (2S,3R)-2-[2-(4-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 80);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 81);-   (2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-phenylpentanoic    acid (Compound No. 82);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-phenylpentanoic    acid (Compound No. 83);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4(trifluoromethyl)phenyl]pentanoic    acid (Compound No. 84);-   (2S,3R)-5-(4-tert-butylphenyl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 85);-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 90);-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 91);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 92);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 93);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 94);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 95);-   (2S,3R)-5-(2′,4′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 97);-   (2S,3R)-2-[2-(6-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 98);-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 99);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-isopropylbiphenyl-4-yl)pentanoic    acid (Compound No. 100);-   (2S,3R)-5-(3′-chloro-4′-fluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 101);-   (2S,3R)-5-(4′-butylbiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 102);-   (2S,3R)-5-(2′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 103);-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 104);-   (2S,3R)-3-hydroxy-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 105);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 106);-   (2S,3R)-5-[6-(3,4-difluorophenyl)pyridin-3-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 107);-   (2S,3R)-5-[6-(4-chloro-3-fluorophenyl)pyridin-3-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 108);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-(4-fluorophenyl)pyridin-3-yl]-3-hydroxypentanoic    acid (Compound No. 109);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-(3-fluoro-4-methylphenyl)pyridin-3-yl]-3-hydroxypentanoic    acid (Compound No. 110);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 111);-   (2S,3R)-2-[2-(8-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 112);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 113);-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 114);-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 115);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 116);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 117);-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 118);-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 119);-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 121);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 122);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 123);-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 124);-   (2S,3R)-3-hydroxy-5-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 125);-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 126);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 127);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 128);-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 129);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 130);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 131);-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 132);-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 133);-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 134);-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 135);-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 136);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 137);-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 138);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 139);-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 140);-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 141);-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 142);-   (2S,3S)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 143);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 144);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 145);-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 146);-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]pentanoic acid (Compound No. 147);-   (2S,3R)-5-[4-(6-chloropyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 148);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic acid    (Compound No. 149);-   (2S,3R)-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic acid    (Compound No. 150);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-5-(4′-methylbiphenyl-4-yl)pentanoic acid (Compound    No. 151);-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 152);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 153);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]pentanoic acid (Compound No. 154);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-3-hydroxypentanoic acid (Compound No. 155);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]pentanoic acid (Compound No. 156);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]pentanoic acid (Compound No. 157);-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 158);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 159);-   (2S,3R)-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic acid    (Compound No. 160);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 161);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic acid    (Compound No. 162);-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 163);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 164);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3    (4H)-yl)ethyl]pentanoic acid (Compound No. 165);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 166);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 167);-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 168);-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 169);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 170);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 171);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 172);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 173);-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 174);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 175);-   (2S,3R)-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)-2-thienyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 176);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 177);-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 178);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 179);-   (2S,3R)-5-[4-(2-chloropyridin-3-yl)phenyl]-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 180);-   (2S,3R)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 181);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 182);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 183);-   (2S,3R)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 184);-   (2S,3R)-3-hydroxy-5-[4-(2-methoxypyrimidin-5-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 185);-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 186);-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 187);-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 188);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 189);-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 190);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 191);-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 192);-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 193);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(2-methoxypyrimidin-5-yl)phenyl]pentanoic    acid (Compound No. 194);-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(2-methoxypyrimidin-5-yl)phenyl]pentanoic    acid (Compound No. 195);-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(1-oxophthalazin-2(1H)-yl)ethyl]pentanoic    acid (Compound No. 196);-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)ethyl]pentanoic    acid (Compound No. 197);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-{2-[4-oxo-7-(trifluoromethyl)-1,2,3-benzotriazin-3(4H)-yl]ethyl}pentanoic    acid (Compound No. 198);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(1-oxophthalazin-2(1H)-yl)ethyl]pentanoic    acid (Compound No. 199);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)ethyl]pentanoic    acid (Compound No. 200);-   (2S,3R)-2-[2-(7,9-dioxo-8-azaspiro[4.5]dec-8-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 201);-   (2S,3R)-2-[2-(2,4-dioxo-2H-1,3-benzoxazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 202);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl]pentanoic    acid (Compound No. 203);-   (2S,3R)-5-(4-chloro-3-fluorophenyl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 204);-   (2R,3S)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 205);-   (2R,3S)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 206);-   (2R,3S)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 207);-   (2S,3S)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 208);-   (2S,3R)-3-hydroxy-5-[4-(5-methylpyridin-2-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 209);-   (2S,3R)-5-[4-(6-fluoropyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 210);-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 211);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 212);-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 213);-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 214);-   (2S,3R)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 215);-   (2S,3R)-5-(2′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 216);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 217);-   (2S,3R)-5-(3′-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 218);-   (2S,3R)-3-hydroxy-5-[4-(2-methoxypyrimidin-5-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 219);-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 220);-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 221);-   (2S,3R)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 222);-   (2S,3R)-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 223);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 224);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 225);-   (2S,3R)-3-hydroxy-5-[4-(6-hydroxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 226);-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-{2-[4-oxo-7-(trifluoromethyl)-1,2,3-benzotriazin-3(4H)-yl]ethyl}pentanoic    acid (Compound No. 227);-   (2S,3R)-2-[2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 228);-   (2S,3R)-3-(acetyloxy)-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 229);-   (2S,3R)-2-[2-(8-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 230);-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(2,4-dioxo-2H-1,3-benzoxazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 231); and-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-(2-{[(2-hydroxyphenyl)carbonyl]amino}ethyl)pentanoic    acid (Compound No. 232).

In another embodiment, the present invention relates to a chiralauxiliary (4S)-4-benzyl-1,3-thiazolidin-2-one which would be ofversatile utility for asymmetric synthesis. Chiral auxiliaries areutilized in a wide variety of synthetic transformations which include,but are not limited to, asymmetric aldol condensation, stereoselectivealkylation, stereoselective Diels-Alder reaction, stereoselectiveMichael reactions, and stereoselective differentiation of enantiotopicgroups in molecules bearing prochiral centers. The chiral auxiliary isused in stoichiometric amounts to induce the stereoselective formationof stereogenic centers.

In another embodiment, the present invention relates to thetherapeutically effective dose of a compound of Formula I in combinationwith one or more other therapeutic agents used for treating variousinflammatory and allergic diseases. Examples of such therapeutic agentsinclude, but are not limited to:

-   -   1) Anti-inflammatory agents, experimental or commercial such        as (i) nonsteroidal anti-inflammatory agents piroxicam,        diclofenac, propionic acids, fenamates, pyrazolones,        salicylates, PDE-4/p38 MAP Kinase/Cathepsin inhibitors, CCR-3        antagonists, iNOS inhibitors, tryptase and elastase inhibitors,        beta-2 integrin antagonists, cell adhesion inhibitors        (especially ICAM), or adenosine 2a agonists; (ii) leukotrienes        LTC4/LTD4/LTE4/LTB4-Inhibitors, 5-lipoxygenase inhibitors, and        PAF-receptor antagonists; (iii) Cox-2 inhibitors; (iv) other MMP        inhibitors; (v) interleukin-1 inhibitors; or (vi)        corticosteroids such as alclometasone, amcinonide,        amelometasone, beclometasone, betamethasone, budesonide,        ciclesonide, clobetasol, cloticasone, cyclomethasone,        deflazacort, deprodone, dexbudesonide, diflorasone,        difluprednate, fluticasone, flunisolide, halometasone,        halopredone, hydrocortisone, methylprednisolone, mometasone,        prednicarbate, prednisolone, rimexolone, tixocortol,        triamcinolone, ulobetasol, rofleponide, GW 215864, KSR 592,        ST-126, dexamethasone, and pharmaceutically acceptable salts or        solvates thereof. Preferred corticosteroids include, for        example, flunisolide, beclomethasone, triamcinolone, budesonide,        fluticasone, mometasone, ciclesonide, and dexamethasone;    -   2) Beta-agonists, experimental or commercial, suitable        132-agonists include, for example, (i) one or more of albuterol,        salbutamol, biltolterol, pirbuterol, levosalbutamol,        tulobuterol, terbutaline, bambuterol, metaproterenol, fenoterol,        salmeterol, carmoterol, arformoterol, or formoterol, and        pharmaceutically acceptable salts or solvates thereof. One or        more β2-agonists may be chosen from those in the art or        subsequently discovered. (ii) The β2-agonists may include one or        more compounds described in, for example, U.S. Pat. Nos.        3,705,233; 3,644,353; 3,642,896; 3,700,681; 4,579,985;        3,994,974; 3,937,838; 4,419,364; 5,126,375; 5,243,076;        4,992,474; and 4,011,258;    -   3) antihypertensive agents, (i) ACE inhibitors, e.g., enalapril,        lisinopril, valsartan, Telmisartan, and quinapril; (ii)        angiotensin II receptor antagonists and agonists, e.g.,        losartan, candesartan, irbesartan, valsartan, and        eprosartan; (iii) β-blockers; and (iv) calcium channel blockers;    -   4) immunosuppressive agents, for example, cyclosporine,        azathioprine, and methotrexate; anti-inflammatory        corticosteroids; and    -   5) anti-infective agents, e.g., antibiotics and antivirals.

DEFINITIONS

The following definitions apply to terms as used herein.

The term “alkyl”, unless otherwise specified, refers to a monoradicalbranched or unbranched saturated hydrocarbon chain having from 1 to 20carbon atoms. Alkyl groups can be optionally interrupted by atoms orgroups independently selected from oxygen, sulfur, a phenylene,sulphinyl, sulphonyl, group or —NR_(α)—, wherein R_(α) can be hydrogen,alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, acyl, aralkyl,—C(═O)OR_(λ), SO_(m)R_(ψ), or —C(═O)NR_(λ)R_(π). This term can beexemplified by groups such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neopentyl,n-hexyl, n-decyl, tetradecyl, and the like. Alkyl groups may besubstituted further with one or more substituents selected from alkenyl,alkynyl, alkoxy, cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy,alkoxycarbonylamino, azido, cyano, halogen, hydroxy, keto, oxo,thiocarbonyl, carboxy, carboxyalkyl, aryl, heterocyclyl, heteroaryl,(heterocyclyl)alkyl, cycloalkoxy, —CH═N—O(C₁₋₆ alkyl),—CH═N—NH(C₁₋₆alkyl), —CH═N—NH(C₁₋₆alkyl)-C₁₋₆alkyl, arylthio, thiol,alkylthio, aryloxy, nitro, aminosulfonyl, aminocarbonylamino,—NHC(═O)R_(λ), —NR_(λ)R_(π), —C(═O)NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π),—C(═O)heteroaryl, C(═O)heterocyclyl, —O—C(═O)NR_(λ)R_(π) {wherein R_(λ)and R_(π) are independently selected from hydrogen, halogen, hydroxy,alkyl, alkenyl, alkynyl, alkenyl, alkoxy, cycloalkyl, cycloalkenyl,aryl, aralkyl, heterocyclyl, heteroaryl, heterocyclylalkyl,heteroarylalkyl, or carboxy}, nitro, or —SO_(m)R_(ψ) (wherein m is aninteger from 0-2 and R_(ψ) is hydrogen, alkyl, alkenyl, alkynyl,cycloalkyl, aralkyl, aryl, heterocyclyl, heteroaryl, heteroarylalkyl, orheterocyclylalkyl). Unless otherwise constrained by the definition,alkyl substituents may be further substituted by 1-3 substituentsselected from alkyl, alkenyl, alkynyl, carboxy, —NR_(λ)R_(π),—C(═O)NR_(λ)R_(π), —OC(═O)NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π), hydroxy,alkoxy, halogen, CF₃, cyano, and —SO_(m)R_(ψ); or an alkyl group alsomay be interrupted by 1-5 atoms of groups independently selected fromoxygen, sulfur or —NR_(α)— (wherein R_(α), R_(λ), R_(π), m, and R_(ψ)are the same as defined earlier). Unless otherwise constrained by thedefinition, all substituents may be substituted further by 1-3substituents selected from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, —NR_(λ)R_(π), —C(═O)NR_(λ)R_(π), —O—C(═O)NR_(λ)R_(π),hydroxy, alkoxy, halogen, CF₃, cyano, and —SO_(m)R_(ψ) (wherein R_(λ),R_(π), m, and R_(ψ) are the same as defined earlier); or an alkyl groupas defined above that has both substituents as defined above and is alsointerrupted by 1-5 atoms or groups as defined above.

The term “alkenyl”, unless otherwise specified, refers to a monoradicalof a branched or unbranched unsaturated hydrocarbon group having from 2to 20 carbon atoms with cis, trans or geminal geometry. Alkenyl groupscan be optionally interrupted by atoms or groups independently chosenfrom oxygen, sulfur, phenylene, sulphinyl, sulphonyl and —NR_(α)—(wherein R_(α) is the same as defined earlier). In the event thatalkenyl is attached to a heteroatom, the double bond cannot be alpha tothe heteroatom. Alkenyl groups may be substituted further with one ormore substituents selected from alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, —NHC(═O)R_(λ),—NR_(λ)R_(π), —C(═O)NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π),—O—C(═O)NR_(λ)R_(π), alkoxycarbonylamino, azido, cyano, halogen,hydroxy, oxo, keto, carboxyalkyl, thiocarbonyl, carboxy, arylthio,thiol, alkylthio, aryl, aralkyl, aryloxy, heterocyclyl, heteroaryl,heterocyclyl alkyl, heteroaryl alkyl, aminosulfonyl, aminocarbonylamino,alkoxyamino, hydroxyamino, alkoxyamino, nitro, or SO_(m)R_(ψ) (whereinR_(λ), R_(π), m and R_(ψ) are as defined earlier). Unless otherwiseconstrained by the definition, alkenyl substituents optionally may besubstituted further by 1-3 substituents selected from alkyl, alkenyl,alkynyl, carboxy, hydroxy, alkoxy, halogen, —CF₃, cyano, —NR_(λ)R_(π),—C(═O)NR_(λ)R_(π), —O—C(═O)NR_(λ)R_(π), and —SO_(m)R_(ψ) (wherein R_(λ),R_(π), m, and R_(ψ) are as defined earlier). Groups, such as ethenyl orvinyl (CH═CH₂), 1-propylene, allyl (—CH₂CH═CH₂), iso-propylene(—C(CH₃)═CH₂), bicyclo[2.2.1]heptene, and the like, exemplify this term.

The term “alkynyl”, unless otherwise specified, refers to a monoradicalof an unsaturated hydrocarbon, having from 2 to 20 carbon atoms. Alkynylgroups can be optionally interrupted by atoms or groups independentlychosen from oxygen, sulfur, phenylene, sulphinyl, sulphonyl, and—NR_(α)— (wherein R_(α) is the same as defined earlier). In the eventthat alkynyl groups are attached to a heteroatom, the triple bond cannotbe alpha to the heteroatom. Alkynyl groups may be substituted furtherwith one or more substituents selected from alkyl, alkenyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, keto, oxo, thiocarbonyl, carboxy,carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy,aminosulfonyl, aminocarbonylamino, hydroxyamino, alkoxyamino, nitro,heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl,—NHC(═O)R_(λ), —NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π), —C(═O)NR_(λ)R_(π),—O—C(═O)NR_(λ)R_(π) or —SO_(m)R_(ψ) (wherein R_(λ), R_(π), m, and R_(ψ)are the same as defined earlier). Unless otherwise constrained by thedefinition, alkynyl substituents optionally may be substituted furtherby 1-3 substituents selected from alkyl, alkenyl, alkynyl, carboxy,carboxyalkyl, hydroxy, alkoxy, halogen, CF₃, —NR_(λ)R_(π),—C(═O)NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π), —C(═O)NR_(λ)R_(π), cyano, or—SO_(m)R_(ψ) (wherein R_(λ), R_(π), m, and R_(ψ) are the same as definedearlier).

The term “cycloalkyl”, unless otherwise specified, refers to cyclicalkyl groups of from 3 to 20 carbon atoms having a single cyclic ring ormultiple condensed rings, which may optionally contain one or moreolefinic bonds, unless otherwise constrained by the definition. Suchcycloalkyl groups can include, for example, single ring structures,including cyclopropyl, cyclobutyl, cyclooctyl, cyclopentenyl, and thelike, or multiple ring structures, including adamantanyl,bicyclo[2.2.1]heptane, or cyclic alkyl groups to which is fused an arylgroup, for example, indane and the like. Spiro and fused ring structurescan also be included. Cycloalkyl groups may be substituted further withone or more substituents selected from alkyl, alkenyl, alkynyl, alkoxy,cycloalkyl, cycloalkenyl, acyl, acylamino, acyloxy, alkoxycarbonylamino,azido, cyano, halogen, hydroxy, oxo, thiocarbonyl, carboxy,carboxyalkyl, arylthio, thiol, alkylthio, aryl, aralkyl, aryloxy,aminosulfonyl, aminocarbonylamino, —NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π),—NHC(═O)R_(λ), —C(═O)NR_(λ)R_(π), —O—C(═O)NR_(λ)R_(π), nitro,heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl, orSO_(m)R_(ψ) (wherein R_(λ), R_(π), m, and R_(ψ) are the same as definedearlier). Unless otherwise constrained by the definition, cycloalkylsubstituents optionally may be substituted further by 1-3 substituentsselected from alkyl, alkenyl, alkynyl, carboxy, hydroxy, alkoxy,halogen, CF₃, —NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π), —NHC(═O)NR_(λ)R_(π),—OC(═O)NR_(λ)R_(π), cyano, or —SO_(m)R_(ψ) (wherein R_(λ), R_(π), m, andR_(ψ) are the same as defined earlier). “Cycloalkylalkyl” refers toalkyl-cycloalkyl group linked through alkyl portion, wherein the alkyland cycloalkyl are the same as defined earlier.

The term “aralkyl”, unless otherwise specified, refers to alkyl-aryllinked through an alkyl portion (wherein alkyl is as defined above) andthe alkyl portion contains 1 to 6 carbon atoms and aryl is as definedbelow. Examples of aralkyl groups include benzyl, ethylphenyl,propylphenyl, naphthylmethyl, and the like.

The term “aryl”, unless otherwise specified, refers to aromatic systemhaving 6 to 14 carbon atoms, wherein the ring system can be mono-, bi-,or tricyclic and are carbocyclic aromatic groups. For example, arylgroups include, but are not limited to, phenyl, biphenyl, anthryl, ornaphthyl ring and the like, optionally substituted with 1 to 3substituents selected from halogen (e.g., F, Cl, Br, I), hydroxy, alkyl,alkenyl, alkynyl, cycloalkyl, alkoxy, acyl, aryloxy, CF₃, cyano, nitro,COOR_(ψ), NHC(═O)R_(λ), —NR_(λ)R_(π), —C(═O)NR_(λ)R_(π),—NHC(═O)NR_(λ)R_(π), —O—C(═O)NR_(λ)R_(π), —SO_(m)R_(ψ), carboxy,heterocyclyl, heteroaryl, heterocyclylalkyl, heteroarylalkyl or aminocarbonyl amino, mercapto, haloalkyl, optionally substituted aryl,optionally substituted heterocyclylalkyl, thioalkyl, —CONHR_(π),—OCOR_(π), —COR_(π), —NHSO₂R_(π), or —SO₂NHR_(π) (wherein R_(λ), R_(π),m, and R_(ψ) are the same as defined earlier). Aryl groups optionallymay be fused with a cycloalkyl group, wherein the cycloalkyl group mayoptionally contain heteroatoms selected from O, N, or S. Groups such asphenyl, naphthyl, anthryl, biphenyl, and the like exemplify this term.

The term “aryloxy” denotes the group O-aryl wherein aryl is the same asdefined above.

The term “heteroaryl”, unless otherwise specified, refers to an aromaticring structure containing 5 or 6 ring atoms or a bicyclic or tricyclicaromatic group having from 8 to 10 ring atoms, with one or moreheteroatoms independently selected from N, O, or S optionallysubstituted with 1 to 4 substituents selected from halogen (e.g., F, Cl,Br, I), hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, carboxy,aryl, alkoxy, aralkyl, cyano, nitro, heterocyclyl, heteroaryl,—NR_(λ)R_(π), CH═NOH, —(CH₂)_(w)C(═O)R_(η) {wherein w is an integer from0 to 4 and R_(η) is hydrogen, hydroxy, OR_(λ), NR_(λ)R_(π), —NHOR_(ω) or—NHOH}, —C(═O)NR_(λ)R_(π)—NHC(═O)NR_(λ)R_(π), —SO_(m)R_(ψ),—O—C(═O)NR_(λ)R_(π), —O—C(═O)R_(λ), or —O—C(═O)OR_(λ) (wherein m, R_(ψ),R_(λ), and R_(π) are as defined earlier and R_(ω) is alkyl, cycloalkyl,aryl, heteroaryl, heterocyclyl, heteroarylalkyl, or heterocyclylalkyl).Unless otherwise constrained by the definition, the substituents areattached to a ring atom, i.e., carbon or heteroatom in the ring.Examples of heteroaryl groups include oxazolyl, imidazolyl, pyrrolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, thiazolyl, oxadiazolyl,benzoimidazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, thienyl, isoxazolyl, triazinyl, furanyl, benzofuranyl,indolyl, benzthiazinyl, benzthiazinonyl, benzoxazinyl, benzoxazinonyl,quinazonyl, carbazolyl phenothiazinyl, phenoxazinyl, benzothiazolyl, orbenzoxazolyl, and the like.

The term “heterocyclyl”, unless otherwise specified, refers to anon-aromatic monocyclic or bicyclic cycloalkyl group having 5 to 10atoms wherein 1 to 4 carbon atoms in a ring are replaced by heteroatomsselected from O, S, or N, and optionally are benzofused or fused with aheteroaryl having 5 to 6 ring members and/or optionally are substituted,wherein the substituents are selected from halogen (e.g., F, Cl, Br, I),hydroxy, alkyl, alkenyl, alkynyl, cycloalkyl, acyl, optionallysubstituted aryl, alkoxy, alkaryl, cyano, nitro, oxo, carboxy,optionally substituted heterocyclyl, optionally substitutedheterocyclylalkyl, optionally substituted heteroaryl, —O—C(═O)Rλ,—O—C(═O)ORλ, —C(═O)NRλRπ, SOmRψ, —O—C(═O)NRλRπ, —NHC(═O)NRλRπ, —NRλRπ,mercapto, haloalkyl, thioalkyl, —COORψ, —COONHRλ, —CORλ, —NHSO2Rλ, orSO2NHRλ (wherein m, Rψ, Rλ, and Rπ are as defined earlier) or guanidine.Heterocyclyl can optionally include rings having one or more doublebonds. Such ring systems can be mono-, bi-, or tricyclic. Carbonyl orsulfonyl group can replace carbon atoms of heterocyclyl. Unlessotherwise constrained by the definition, the substituents are attachedto the ring atom, i.e., carbon or heteroatom in the ring. Also, unlessotherwise constrained by the definition, the heterocyclyl ringoptionally may contain one or more olefinic bonds. Examples ofheterocyclyl groups include benzotriazinone, isoindoledione,pyrimidinedione, aza-spiro[4.5]decanedione, benzo-oxazinedione,imidazolidinedione, phthalazinone, oxazolidinyl, tetrahydrofuranyl,dihydrofuranyl, benzoxazinyl, benzthiazinyl, imidazolyl, benzimidazolyl,tetrazolyl, carbaxolyl, indolyl, phenoxazinyl, phenothiazinyl,dihydropyridinyl, dihydroisoxazolyl, dihydrobenzofuryl, azabicyclohexyl,thiazolidinyl, dihydroindolyl, pyridinyl, isoindole 1,3-dione,piperidinyl, tetrahydropyranyl, piperazinyl, 3H-imidazo[4,5-b]pyridine,isoquinolinyl, 1H-pyrrolo[2,3-b]pyridine, or piperazinyl, and the like.

The term “cycloalkylalkyl” refers to cycloalkyl group linked throughalkyl portion, wherein the alkyl having 1 to 6 carbon atoms andcycloalkyl are the same as defined earlier.

The term “heteroarylalkyl” refers to heteroaryl group linked throughalkyl portion, wherein the alkyl having 1 to 6 carbon atoms andheteroaryl are the same as defined earlier.

The term “heterocyclylalkyl” refers to heterocyclyl group linked throughalkyl portion, wherein the alkyl having 1 to 6 carbon atoms andheterocyclyl are the same as defined earlier.

The term “amino” refers to —NH₂.

The term “acyl” refers to —C(═O)R₄ wherein R₄ is the same as definedearlier.

The term “thioacyl” refers to —C(═S)R₄ wherein R₄ is the same as definedabove.

The term “halogen” refers to fluorine, chlorine, bromine, or iodine.

The term “leaving group” refers to groups that exhibit or potentiallyexhibit the properties of being labile under the synthetic conditionsand also of being readily separated from synthetic products underdefined conditions. Examples of leaving groups include, but are notlimited to, halogen (e.g., F, Cl, Br, I), triflates, tosylate,mesylates, alkoxy, thioalkoxy, or hydroxy radicals, and the like.

The term “protecting groups” refers to moieties that prevent chemicalreaction at a location of a molecule intended to be left unaffectedduring chemical modification of such molecule. Unless otherwisespecified, protecting groups may be used on groups, such as hydroxy,amino, or carboxy. Examples of protecting groups are found in T. W.Greene and P. G. M. Wuts, “Protective Groups in Organic Synthesis”,2^(nd) Ed., John Wiley and Sons, New York, N.Y., which is incorporatedherein by reference. The species of the carboxylic protecting groups,amino protecting groups, or hydroxy protecting groups employed are notcritical, as long as the derivatised moiety/moieties is/are stable toconditions of subsequent reactions and can be removed without disruptingthe remainder of the molecule.

Compounds described herein can contain one or more asymmetric carbonatoms and thus occur as diastereomers. These compounds can also exist asconformers/rotamers. All such isomeric forms of these compounds areincluded herein. Each stereogenic carbon may be of the R or Sconfiguration. Although the specific compounds exemplified in thisapplication may be depicted in a particular stereochemicalconfiguration, compounds having either the opposite stereochemistry atany given chiral center, or mixtures thereof, are envisioned.

The term “pharmaceutically acceptable salts” forming part of thisinvention includes the salts of carboxylic acid moiety, which may beprepared by reacting the compound with appropriate base to providecorresponding base addition salts. Examples of such bases are alkalimetal hydroxides including potassium hydroxide, sodium hydroxide andlithium hydroxide; or alkaline earth metal hydroxides such as magnesiumhydroxide and calcium hydroxide. Further, the salts of organic basessuch as lysine, arginine, guanidine, ethanolamine, choline, and thelike; inorganic bases, e.g., ammonium or substituted ammonium salts arealso included. Wherever appropriate, compounds of the present inventionmay also form the acid addition salts by treating the said compoundswith pharmaceutically acceptable organic and inorganic acids, e.g.,hydrohalides such as hydrochloride, hydrobromide, or hydroiodide; othermineral acids and their corresponding salts such as sulphate, nitrate,phosphate, etc.; and alkyl and mono-arylsulphonates such as ethanesulphonate, toluene sulphonate, and benzene sulphonate; and otherorganic acids and their corresponding salts such as acetate, tartarate,maleate, succinate, citrate, etc.

The salt forms differ from the compound described herein in certainphysical properties such as solubility, but the salts are otherwiseequivalent for the purpose of this invention.

The term “pharmaceutically acceptable solvates” refers to solvates withwater (i.e., hydrates) or pharmaceutically acceptable solvents, forexample, solvates with ethanol and the like. Such solvates are alsoencompassed within the scope of the disclosure. Furthermore, some of thecrystalline forms for compounds described herein may exist as polymorphsand as such are intended to be included in the scope of the disclosure.

The term “polymorphs” includes all crystalline forms as well asamorphous forms for compounds described herein, and as such are includedin the present invention.

The phrase “pharmaceutically acceptable carriers” is intended to includenon-toxic, inert solid, semi-solid, or liquid filler, diluent,encapsulating material, or formulation auxiliary of any type.

The term “pharmaceutically acceptable” means approved by regulatoryagency of the federal or a state government or listed in the U.S.Pharmacopoeia or other generally recognized pharmacopoeia for use inanimals, and more particularly, in humans.

Examples of inflammatory conditions and autoimmune disorders in whichthe compounds of the invention have potentially beneficial effects intreatment methods may include, but are not limited to, diseases of therespiratory tract such as asthma (including allergen-induced asthmaticreactions), cystic fibrosis, bronchitis (including chronic bronchitis),chronic obstructive pulmonary disease (COPD), adult respiratory distresssyndrome (ARDS), chronic pulmonary inflammation, rhinitis and upperrespiratory tract inflammatory disorders (URID), ventilator induced lunginjury, silicosis, pulmonary sarcoidosis, idiopathic pulmonary fibrosis,bronchopulmonary dysplasia, arthritis, e.g., rheumatoid arthritis,osteoarthritis, infectious arthritis, psoriatic arthritis, traumaticarthritis, rubella arthritis, Reiter's syndrome, gouty arthritis, andprosthetic joint failure, gout, acute synovitis, spondylitis, andnon-articular inflammatory conditions, e.g.,herniated/ruptured/prolapsed intervertebral disk syndrome, bursitis,tendonitis, tenosynovitic, fibromyalgic syndrome, and other inflammatoryconditions associated with ligamentous sprain and regionalmusculoskeletal strain, inflammatory disorders of the gastrointestinaltract, e.g., ulcerative colitis, diverticulitis, Crohn's disease,inflammatory bowel diseases, irritable bowel syndrome, and gastritis,multiple sclerosis, systemic lupus erythematosus, scleroderma,autoimmune exocrinopathy, autoimmune encephalomyelitis, diabetes, tumorangiogenesis and metastasis, cancer including carcinoma of the breast,colon, rectum, lung, kidney, ovary, stomach, uterus, pancreas, liver,oral, laryngeal, and prostate, melanoma, acute and chronic leukemia,periodontal disease, neurodegenerative disease, Alzheimer's disease,Parkinson's disease, epilepsy, muscle degeneration, inguinal hernia,retinal degeneration, diabetic retinopathy, macular degeneration,inguinal hernia, ocular inflammation, bone resorption diseases,osteoporosis, osteopetrosis, graft vs. host reaction, allograftrejections, sepsis, endotoxemia, toxic shock syndrome, tuberculosis,usual interstitial and cryptogenic organizing pneumonia, bacterialmeningitis, systemic cachexia, cachexia secondary to infection ormalignancy, cachexia secondary to acquired immune deficiency syndrome(AIDS), malaria, leprosy, leishmaniasis, Lyme disease,glomerulonephritis, glomerulosclerosis, renal fibrosis, liver fibrosis,pancrealitis, hepatitis, endometriosis, pain, e.g., that associated withinflammation and/or trauma, inflammatory diseases of the skin, e.g.,dermatitis, dermatosis, skin ulcers, psoriasis, eczema, systemicvasculitis, vascular dementia, thrombosis, atherosclerosis, restenosis,reperfusion injury, plaque calcification, myocarditis, aneurysm, stroke,pulmonary hypertension, left ventricular remodeling, and heart failure.It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofestablished conditions.

Compounds disclosed herein may be prepared, for example, by techniqueswell known in the organic synthesis and familiar to a practitionerordinarily skilled in art of this invention. In addition, the processesdescribed herein may enable the synthesis of the compounds of thepresent invention. However, these may not be the only means by which thecompounds described in the invention may be synthesized. Further, thevarious synthetic steps described herein may be performed in alternatesequences in order to furnish the desired compounds.

Compounds of Formulae VIIIa and VIIIb can be prepared by following, forexample, synthetic routes as depicted in Scheme I. Thus, a compound ofFormula II can be converted to a compound of Formula III (wherein P₁ isa silyl protecting group for example, tert-butyldimethylsilane,tert-butyldiphenylsilane, or triisopropylsilane), which can then beconverted to a compound of Formula IV (wherein P₁ is defined as aboveand R′ and R″ together form an acetal protecting group, for example,isopropylidene or cyclohexylidene acetal). The compound of Formula IVcan be oxidized to form a compound of Formula V. The compound of FormulaV can then be converted to a compound of Formula VI (wherein E is analkyl group such as methyl, ethyl, and the like), which can then behydrogenated to form compounds of Formulae VIIa and VIIb. Compounds ofFormulae VIIa and VIIb can be reduced to form compounds of FormulaeVIIIa and VIIIb.

Silylation of a compound of Formula II to form a compound of Formula IIIcan be carried out with silylating reagents such as, for example,tert-butyldimethylchlorosilane, triphenylchlorosilane,t-butyldiphenylchlorosilane in the presence of a base, for example,imidazole or triethylamine in an organic solvent, for example, dimethylformamide, dimethylsulphoxide or acetonitrile.

Acetonation of a compound of Formula III to form a compound of FormulaIV can be carried out with excess acetone as a solvent, in the presenceof a mild acid catalyst, for example, anhydrous copper (II) sulphate andcamphorsulphonic acid, anhydrous zinc chloride and a small amount ofphosphoric acid, or anhydrous ferric chloride. Alternately, one mayutilize trans-acetonation with dimethoxypropane in the presence of acidcatalysts such as p-toluenesulfonic acid, sulfuric acid, ormontmorillonite-K.

The compound of Formula IV can be oxidized to form a compound of FormulaV, for example, by using Swern oxidation (dimethylsulphoxide and oxalylchloride) or Corey-Kim oxidation (N-chlorosuccinimide anddimethylsulphide) in the presence of a base, for example, triethylamine,diisopropylethylamine in a solvent, for example, dichloromethane ortoluene. Alternatively, the compound of Formula IV can be oxidized to acompound of Formula V in, for example, dichloromethane or chloroformwith an oxidizing agent, such as Dess-Martin reagent, pyridiniumchlorochromate (PCC), or pyridinium dichromate (PDC). Oxidation of thecompound of Formula IV to form a compound of Formula V can also becarried out catalytically using, for example,2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) and the 4-substitutedderivatives thereof, including, for example, 4-methoxy-TEMPO,4-ethoxy-TEMPO, 4-acetoxy-TEMPO, 4-acetamino-TEMPO, 4-hydroxy-TEMPO,4-benzoyloxy-TEMPO, 4-amino-TEMPO, N,N-dimethylamino-TEMPO, or4-oxo-TEMPO as a catalyst, in the presence of a co-catalyst, forexample, potassium bromide or sodium bromide, with an oxidant, forexample, sodium hypochlorite, potassium hypochlorite, calciumhypochlorite, sodium hypobromite, or potassium hypobromite in a solvent,for example, methylene chloride, chloroform, ethyl acetate, butylacetate, acetonitrile, tetrahydrofuran, toluene, acetone, diethyl ether,methyl tert-butyl ether, pentane, hexane, or mixtures of such solvents.

The compound of Formula V can be converted to a compound of Formula VI,for example, via a Horner-Wadsworth-Emmons reaction, thus a compound ofFormula V can be reacted with phosphonate carbanions produced in situ bytreating trimethylphosphonoacetate or triethylphosphonoacetate with abase, for example, sodium hydride, potassium hydride, potassiumtert-butoxide, sodium tert-butoxide, potassium carbonate, triethylaminein an organic solvent, for example, tetrahydrofuran or dimethoxyethaneto give a compound of Formula VI. Alternately, the Wittig reaction canbe carried out using the preformed Wittig reagent such as(carboethoxymethylene)-triphenylphosphorane.

Hydrogenation of a compound of Formula VI to form compounds of FormulaeVIIa and VIIb can be carried with palladium on carbon in the presence ofhydrogen, in a suitable solvent, for example, methanol, ethanol,propanol, tetrahydrofuran, ethyl acetate, or mixtures thereof.

Compounds of Formulae VIIa and VIIb can be reduced to give compounds ofFormula VIIIa and VIIIb in the presence of a reducing agent, forexample, lithium aluminum hydride, lithium triethyl borohydride, orsodium borohydride, in the presence of an additive, for example, lithiumchloride or aluminum chloride, in an organic solvent, for example,tetrahydrofuran, diethylether, or diglyme.

Compounds of Formula XX can be prepared, for example, by followingsynthetic routes as depicted in Scheme II. Thus, a compound of FormulaVIIIa (wherein P₁, R′, and R″ are same as defined earlier), can reactwith a compound of Formula IX (wherein R₂ is an N-containingheterocyclyl or heteroaryl) to give a compound of Formula X. Thecompound of Formula X can undergo deprotection to form a compound ofFormula XI which, on oxidation, can give a compound of Formula XII. Thecompound of Formula XII on reaction with a compound of Formula XIII(wherein Q is same as defined earlier, hal is Cl, Br, or I and Ar isphenyl) can form a compound of Formula XIV. The compound of Formula XIVcan then react with a compound of Formula XV (wherein R₁ is same asdefined earlier) to form a compound of Formula XVI which can then behydrogenated to form a compound of Formula XVII. The compound of FormulaXVII can undergo deprotection to form a compound of Formula XVIII whichcan then be oxidatively cleaved to form a compound of Formula XIX. Thecompound of Formula XIX can be deformylated to form a compound ofFormula XX.

The reaction of a compound of Formula VIIIa with a compound of FormulaIX to give a compound of Formula X can be carried out usingtriphenylphosphine or tributylphosphine and diethyl azodicarboxylate,diisoproyl azodicarboxylate, or 1,1′-azodicarbonyldipiperidine in anorganic solvent, for example, tetrahydrofuran, dimethylformamide, ortoluene.

The compound of Formula X can be deprotected to form a compound ofFormula XI with deprotecting agents, for example, tetrabutylammoniumfluoride or potassium fluoride in an organic solvent, for example,tetrahydrofuran, dimethylformamide, diethyl ether, or dioxane,optionally in the presence of crown ethers such as, for example,18-crown-6. The oxidation of a compound of Formula XI to give a compoundof Formula XII can be carried out similarly to the oxidation of acompound of Formula IV to form a compound of Formula V.

The compound of Formula XII can be converted to a compound of FormulaXIV by reacting with a compound of Formula XIII (Wittig reagent, i.e.,an ylide, prepared by reacting a phosphonium salt, in turn prepared fromtriphenylphosphine and alkyl halide, in a solvent, for example,tetrahydrofuran, dimethyl sulphoxide, or diethyl ether, with a strongbase, for example, n-butyllithium, sodium hydride, or potassiumtert-butoxide).

The reaction of a compound of Formula XIV with a compound of Formula XVcan be carried out in the presence of a metal catalyst, for example,tetrakis(triphenylphosphine) palladium (0),tetrakis(tricyclohexylphosphine) palladium (0),tetrakis(tri-tert-butylphosphine) palladium (0), or palladium acetateand triphenylphosphine in the presence of a base, for example, potassiumcarbonate or cesium carbonate, in an organic solvent, for example,toluene, dimethyl sulphoxide, dimethylformamide, tetrahydrofuran,dioxane, or diethyl ether.

Hydrogenation of a compound of Formula XVI to form a compound of FormulaXVII can be carried out similarly to hydrogenation of a compound ofFormula VI to compounds of Formulae VIIa and VIIb.

The compound of Formula XVII can be deprotected to form a compound ofFormula XVIII with perchloric acid, acetic acid, or hydrochloric acid insolvent(s), for example, acetonitrile, water, tetrahydrofuran, ormixtures thereof.

Conversion of a compound of Formula XVIII to form a compound of FormulaXIX can be carried out by diol cleavage in the presence of, for example,sodium metaperiodate, lead tetraacetate, pyridinium chlorochromate, ormanganese dioxide, in co-solvents, for example, tert-butanol-water,methanol-tetrahydrofuran, or tert-butanol-tetrahydrofuran, followed byoxidation with, for example, potassium permanganate or with a mixture ofsodium dihydrogen phosphate, sodium chlorite, and hydrogen peroxide.

The compound of Formula XIX can be deformylated to form a compound ofFormula XX in the presence of a base for example, potassium carbonate,sodium carbonate, or triethylamine in a solvent, for example, methanol,tetrahydrofuran, or mixtures thereof.

Compounds of Formula XXVI can be prepared by following synthetic routes,for example, as depicted in Scheme III. Thus, a compound of Formula XIIcan react with a compound of Formula XXI (wherein Q is same as definedearlier and Ar is phenyl) to form a compound of Formula XXII (wherein R₂is an N-containing heterocyclyl or heteroaryl), which can further behydrogenated to form a compound of Formula XXIII. The compound ofFormula XXIII can be deprotected to form a compound of Formula XXIV,which can then be oxidatively cleaved to give a compound of Formula XXV.The compound of Formula XXV can then be deformylated to form a compoundof Formula XXVI.

The reaction of a compound of Formula XII with a compound of Formula XXIto form a compound of Formula XXII can be carried out similarly toreaction of a compound of Formula XII to a compound of Formula XIV.Hydrogenation of a compound of Formula XXII to give a compound ofFormula XXIII can be carried out under similar conditions as that ofhydrogenation of a compound of Formula VI to compounds of Formulae VIIaand VIIb.

Deprotection of a compound of Formula XXIII to give a compound ofFormula XXIV can be carried out similarly to deprotection of a compoundof Formula XVII to a compound of Formula XVIII. The oxidative cleavageof a compound of Formula XXIV to form a compound of Formula XXV can becarried out under similar condition as that of cleavage of a compound ofFormula XVIII to a compound of Formula XIX.

Deformylation of a compound of Formula XXV to form a compound of FormulaXXVI can be carried out similarly to deformylation of a compound ofFormula XIX to give a compound of Formula XX.

Compounds of Formula XXXV can be prepared by, for example, followingsynthetic routes as depicted in Scheme IV. Thus, a compound of FormulaVIIIb (wherein P₁, R′, and R″ are the same as defined earlier), canreact with a compound of Formula IX (wherein R₂ is an N-containingheterocyclyl or heteroaryl) to give a compound of Formula XXVII. Thecompound of Formula XXVII can be deprotected to form a compound ofFormula)(XVIII, which on oxidation can give a compound of Formula XXIX.The compound of Formula XXIX on reaction with a compound of Formula XIIIcan form a compound of Formula XXX which can then react with a compoundof Formula XV (wherein R₁ is same as defined earlier) to form a compoundof Formula XXXI. The compound of Formula XXXI can then be hydrogenatedto form a compound of Formula XXXII which can then undergo deprotectionto form a compound of Formula XXXIII. The compound of Formula XXXIII canbe oxidatively cleaved to form a compound of Formula XXXIV. The compoundof Formula XXXIV can then be deformylated to form a compound of FormulaXXXV.

The reaction of a compound of Formula VIIIb with a compound of FormulaIX to give a compound of Formula XXVII can be carried out similarly tothe reaction of a compound of Formula VIIIa to form a compound ofFormula X.

Deprotection of a compound of Formula XXVII to give a compound ofFormula XXVIII can be carried out similarly to the deprotection of acompound of Formula X to form a compound of Formula XI.

Oxidation of a compound of Formula XXVIII to give a compound of FormulaXXIX can be carried out similarly to the oxidation of a compound ofFormula IV to form a compound of Formula V.

The reaction of a compound of Formula XXIX with a compound of FormulaXIII to form a compound of Formula XXX can be carried out under similarcondition as that of reaction of a compound of Formula XII to form acompound of Formula XIV.

Coupling of a compound of Formula XXX with a compound of Formula XV toform a compound of Formula XXXI can be carried out similarly to thecoupling of a compound of Formula XIV to form a compound of Formula XVI.

Hydrogenation of a compound of Formula XXXI to form a compound ofFormula XXXII can be carried out similarly to hydrogenation of acompound of Formula VI to form compounds of Formulae VIIa and VIIb. Thecompound of Formula XXXII can be deprotected to form a compound ofFormula XXXIII under similar conditions as that of deprotection of acompound of Formula XVII to form a compound of Formula XVIII.

Oxidative cleavage of a compound of Formula XXXIII to form a compound ofFormula XXXIV can be carried out similarly to cleavage of a compound ofFormula XVIII to give a compound of Formula XIX.

Deformylation of a compound of Formula XXXIV to form a compound ofFormula XXXV can be carried out under similar conditions as that of thedeformylation of a compound of Formula XIX to form a compound of FormulaXX.

Compounds of Formula LIII can be prepared, for example, by followingsynthetic routes as depicted in Scheme V. Thus, a compound of FormulaXXXVI (wherein R₇ and R₈ together form a acetal protecting group, forexample, isopropylidene acetal, and R′ and R″ are the same as describedearlier) can be oxidized to form a compound of Formula XXXVII which canthen be converted to form a compound of Formula XXXVIII (wherein R₉ isalkyl or aryl). The compound of Formula XXXVIII can be hydrogenated togive a compound of Formula XXXIX which can then be hydrolyzed to give acompound of Formula XL. The compound of Formula XL can be oxidized togive a compound of Formula XLI which can then be converted to form acompound of Formula XLII. The compound of Formula XLII can behydrogenated to form a compound of Formula XLIII which can then bereduced to form a compound of Formula XLIV. The compound of Formula XLIVcan then be reacted with a compound of Formula IX (wherein R₂ is anN-containing heterocyclyl or heteroaryl) to afford a compound of FormulaXLV which can then be deprotected to form a compound of Formula XLVI.The compound of Formula XLVI can be oxidized to form a compound ofFormula XLVII which can then react with a compound of Formula XIII toform a compound of Formula XLVIII. The compound of Formula XLVIII canthen be reacted with a compound of Formula XV (wherein R₁ is same asdefined earlier) to give a compound of Formula XLIX which can then behydrogenated to form a compound of Formula L. The compound of Formula Lis deprotected to form a compound of Formula LI which can then beoxidatively cleaved to form a compound of Formula LII. The compound ofFormula LII is then deformylated to form a compound of Formula LIII.

Oxidation of a compound of Formula)(XXVI to form a compound of FormulaXXXVII can be carried out under similar condition as that of oxidationof a compound of Formula IV to form a compound of Formula V. Thecompound of Formula XXXVII can be converted to a compound of FormulaXXXVIII in the presence of, for example, acetic anhydride or benzoicanhydride in presence of base, such as, for example, pyridine,triethylamine, or morpholine.

The compound of Formula XXXVIII can be hydrogenated to form a compoundof Formula XXXIX similarly to the hydrogenation of a compound of FormulaVI to give compounds of Formulae VIIa and VIIb. The hydrolysis of acompound of Formula XXXIX to form a compound of Formula XL can becarried out with a base, for example, sodium hydroxide, potassiumhydroxide, sodium carbonate, potassium carbonate, or sodium methoxide inthe presence of a solvent, for example, methanol, ethanol, orisopropanol. The compound of Formula XL can be oxidized to form acompound of Formula XLI similarly to the oxidation of a compound ofFormula IV to form a compound of Formula V.

Conversion of a compound of Formula XLI to form a compound of FormulaXLII can be carried out under similar condition as that of conversion ofa compound of Formula V to form a compound of Formula VI. The compoundof Formula XLII can be hydrogenated to form a compound of Formula XLIIIsimilarly to the hydrogenation of a compound of Formula VI to compoundsof Formulae VIIa and VIIb. The reduction of a compound of Formula XLIIIto form a compound of Formula XLIV can be carried out under similarcondition as that of reduction of compounds of Formulae VIIa and VIIb toform compounds of Formulae VIIIa and VIIIb. The reaction of a compoundof Formula XLIV with a compound of Formula IX to form a compound ofFormula XLV can be carried out similarly to the reaction of a compoundof Formula VIIIa to form a compound of Formula X.

Selective acetonide deprotection of a compound of Formula XLV to form acompound of Formula XLVI can be carried out with perchloric acid in asolvent, for example, tetrahydrofuran or diethyl ether ortrifluoroacetic acid in dichloromethane. Oxidation of a compound ofFormula XLVI to form a compound of Formula XLVII can be carried outwith, for example, sodium metaperiodate, lead tetraacetate, pyridiniumchlorochromate, or manganese dioxide in a solvent, for example, acetone,methanol, ethanol, or tert-butanol.

The reaction of a compound of Formula XLVII with a compound of FormulaXIII to form a compound of Formula XLVIII can be carried out similarlyto the reaction of a compound of Formula XII to form a compound ofFormula XIV. Coupling of a compound of Formula XLVIII with a compound ofFormula XV to form a compound of Formula XLIX can be carried outsimilarly to the coupling of a compound of Formula XIV to form acompound of Formula XVI. The compound of Formula XLIX can behydrogenated to form a compound of Formula L under similar conditions tothe hydrogenation of a compound of Formula VI to compounds of FormulaeVIIa and VIIb. Deprotection of a compound of Formula L to give acompound of Formula LI can be carried out under similar conditions tothe deprotection of a compound of Formula XVII to form a compound ofFormula XVIII.

The oxidative cleavage of a compound of Formula LI to form a compound ofFormula LII can be done similarly to the cleavage of a compound ofFormula XVIII to form a compound of Formula XIX. The compound of FormulaLII can be deformylated to a compound of Formula LIII under similarconditions as that of deformylation of a compound of Formula XIX to forma compound of Formula XX.

Compounds of Formula LXVI can be prepared, for example, by followingsynthetic routes as depicted in Scheme VI. Thus, a compound of FormulaXXXVII (wherein R₇, R₈, R′, and R″ are same as described earlier) can beconverted to form a compound of Formula LIV which can then behydrogenated to form a compound of Formula LV. The compound of FormulaLV can be selectively deprotected to form a compound of Formula LVIwhich on oxidation, can form a compound of Formula LVII. The compound ofFormula LVII can be reacted with a compound of Formula XIII to form acompound of Formula LVIII which can then be coupled with a compound ofFormula XV (wherein R₁ is same as defined earlier) to give a compound ofFormula LIX. The compound of Formula LIX can be hydrogenated to form acompound of Formula LX which can then be reduced to form a compound ofFormula LXI. The compound of Formula LXI can be activated to form acompound of Formula LXII (wherein U is an O-activating group, forexample, mesyl, tosyl, or triflate), which can then be reacted with acompound of Formula IXa (wherein R₂ is an N-containing heterocyclyl orheteroaryl and M is a metal, for example, potassium, lithium, or sodium)to form a compound of Formula LXIII. The compound of Formula LXIII canthen be deprotected to form a compound of Formula LXIV which can beoxidatively cleaved to form a compound of Formula LXV. The compound ofFormula LXV can be deformylated to form a compound of Formula LXVI.

The compound of Formula XXXVII can be converted to form a compound ofFormula LIV under similar conditions as that of conversion of a compoundof Formula V to form a compound of Formula VI. Hydrogenation of acompound of Formula LIV to form a compound of Formula LV can be carriedout similarly to the hydrogenation of a compound of Formula VI to formcompounds of Formulae VIIa and VIIb.

The compound of Formula LV can be selectively deprotected to form acompound of Formula LVI under similar conditions as that of thedeprotection of a compound of Formula XLV to give a compound of FormulaXLVI. The compound of Formula LVI can be oxidized to form a compound ofFormula LVII similarly to the oxidation of a compound of Formula XLVI toform a compound of Formula XLVII.

The reaction of a compound of Formula LVII with a compound of FormulaXIII to form a compound of Formula LVIII can be carried out undersimilar conditions to the reaction of a compound of Formula XII to forma compound of Formula XIV. The compound of Formula LVIII can be coupledwith a compound of Formula XV to give a compound of Formula LIX undersimilar conditions as that of the coupling of a compound of Formula XIVto form a compound of Formula XVI. Hydrogenation of a compound ofFormula LIX to form a compound of Formula LX can be carried out undersimilar conditions as that of hydrogenation of a compound of Formula VIto form compounds of Formulae VIIa and VIIb.

The compound of Formula LX can be reduced to form a compound of FormulaLXI under similar conditions as that of reduction of compounds ofFormulae VIIa and VIIb to form compounds of Formulae VIIIa and VIIIb.

A compound of Formula LXI can be activated to form a compound of FormulaLXII in a solvent, for example, dichloromethane, toluene, ordichloroethane, using a base, for example, triethylamine,diisopropylamine, or N-methylmorpholine, using a suitable sulphonylchloride, for example, methanesulphonyl chloride or p-toluene sulphonylchloride. The reaction of a compound of Formula LXII with a compound ofFormula IXa to yield a compound of Formula LXIII can be carried out inan organic solvent, for example, tetrahydrofuran, dimethyl sulphoxide,dimethylformamide, acetonitrile, dioxane, or dimethylacetamide.Alternatively, the reaction of a compound of Formula LXII with acompound of Formula IX to yield a compound of Formula LXIII can becarried out in the presence of a base, for example, sodium hydride,potassium tert-butoxide, sodium (m) ethoxide in an organic solvent, forexample, tetrahydrofuran, dimethyl sulphoxide, dimethylformamide,acetonitrile, dioxane, or dimethylacetamide. Alternatively, a compoundof Formula LXI can be converted to a compound of Formula LXIII followingsimilar protocols as that of the reaction of a compound of Formula VIIIawith a compound of Formula IX to give a compound of Formula X.

The compound of Formula LXIII can be deprotected to form a compound ofFormula LXIV similarly to the deprotection of a compound of Formula XVIIto form a compound of Formula XVIII.

The oxidative cleavage of a compound of Formula LXIV to give a compoundof Formula LXV can be done similarly to the cleavage of a compound ofFormula XVIII to form a compound of Formula XIX. The compound of FormulaLXV can be deformylated to form a compound of Formula LXVI under similarcondition as that of deformylation of a compound of Formula XIX to forma compound of Formula XX.

Compounds of Formula XX can also be prepared, for example, by followingalternate synthetic routes as depicted in Scheme VII. Thus, a compoundof Formula LXVII can be coupled with a compound of Formula LXVIII toform a compound of Formula LXIX (wherein R₁ and Q are same as definedearlier), which can then be converted to a compound of Formula LXX (PathA) (wherein E is same as defined earlier). Alternately, the compound ofFormula LXVIIa can undergo esterification to give a compound of FormulaLXIXa, which can be coupled with the compound of Formula XV to form thecompound of Formula LXX (Path B) (wherein E is same as defined earlier).The compound of Formula LXX can be hydrogenated to form the compound ofFormula LXXI, which can then be reduced to form a compound of FormulaLXXII. The compound of Formula LXXII can be oxidized to form a compoundof Formula LXXIII, which can then react with a compound of Formula LXXIV(wherein, when R₂ is N-containing heterocyclyl or heteroaryl, Y and Wcan be oxygen or sulphur, R₁₀ can be alkyl, aryl, or aralkyl, and n isas defined earlier) to form a compound of Formula LXXV. The compound ofFormula LXXII can be further hydrolysed to form a compound of FormulaXX.

Coupling of a compound of Formula LXVII with a compound of FormulaLXVIII to form a compound of Formula LXIX can be carried out similarlyto the coupling of a compound of Formula XIV to form a compound ofFormula XVI.

Conversion of a compound of Formula LXIX to form a compound of FormulaLXX can be carried out under similar conditions to the conversion of acompound of Formula V to form a compound of Formula VI. Esterificationof compound of Formula LXVIIIa to gives a compound of Formula LXIXa canbe carried out in a solvent, for example, methanol, ethanol,tert-butanol, or benzyl alcohol with a halogenating agent, for example,thionyl chloride or oxalyl chloride. Coupling of a compound of FormulaLXIXa with a compound of Formula XV to form a compound of Formula LXXcan be carried out similarly to the coupling of a compound of FormulaXIV to form a compound of Formula XVI.

The compound of Formula LXX can be hydrogenated to form a compound ofFormula LXXI similarly to the hydrogenation of a compound of Formula VIto form compounds of Formulae VIIa and VIIb. The reduction of a compoundof Formula LXXI to form a compound of Formula LXXII can be carried outunder similar conditions as that of reduction of compounds of FormulaeVIIa and VIIb to form compounds of Formulae VIIIa and VIIIb. Thecompound of Formula LXXII can be oxidized to form a compound of FormulaLXXIII similarly to the oxidation of a compound of Formula IV to form acompound of Formula V.

The asymmetric aldol addition of a compound of Formula LXXIII with acompound of Formula LXXIV to form a compound of Formula LXXIV can becarried out by generating the enolates with titanium chloride, dibutylboron triflate, dialkyl boron chloride, or tin(II) triflate, in thepresence of a base, for example, diisopropylethylamine,tetramethylethelenediamine, tributylamine, N-ethylpiperidine,1,4-diazabicyclo[2.2.2]octane, 1,8-Diazabicyclo[5.4.0]undec-7-ene,tetramethylpropylenediamine, or (−) sparteine, in a solvent, forexample, dichloromethane or diethyl ether.

Hydrolysis of a compound of Formula LXXIV to form a compound of FormulaXX can be carried out with hydrogen peroxide and lithium hydroxide, inthe presence of a solvent, for example, tetrahydrofuran, water, ormixtures thereof.

Compound Nos. 1 to 81; 86-88; 90-95; 97-119; 121-142; 144-203; 211-213;and 226-232 were prepared following Schemes I and II. Compound Nos. 82to 85 and 204 were prepared following Schemes I, II, and III. CompoundNos. 143 and 208 were prepared following Scheme IV. Compound Nos. 120and 205-207 were prepared following Scheme V. Compound Nos. 89 and 96were prepared following Scheme VI. Compound Nos. 86; 209-210; and214-225 were prepared following Scheme VII.

In the above schemes, where specific bases, acids, solvents, condensingagents, reducing agents, deprotecting agents, hydrolyzing agents, metalcatalysts, etc., are mentioned, it is to be understood that other acids,bases, solvents, condensing agents, reducing agents, deprotectingagents, hydrolyzing agents, metal catalysts, etc., known to thoseskilled in the art may also be used. Similarly, the reaction temperatureand duration of the reactions may be adjusted according to therequirements that arise during the process.

The following examples are set forth to demonstrate general syntheticprocedures for the preparation of representative compounds of thepresent invention. The examples are provided to illustrate a particularaspect of the disclosure and do not limit the scope of the presentinvention.

EXAMPLES Synthesis of Starting Materials Synthesis of6-methyl-1,2,3-benzotriazin-4(3H)-one

The title compound was prepared following the procedure outlined in J.Med. Chem., 35(14), 2626-2630 (1992).

The following analogues of 6-methyl-1,2,3-benzotriazin-4(3H)-one wereprepared analogously:

-   8-methyl-1,2,3-benzotriazin-4(3H)-one;-   7-methyl-1,2,3-benzotriazin-4(3H)-one;-   6-methyl-1,2,3-benzotriazin-4(3H)-one;-   8-methoxy-1,2,3-benzotriazin-4(3H)-one;-   6-methoxy-1,2,3-benzotriazin-4(3H)-one;-   8-chloro-1,2,3-benzotriazin-4(3H)-one;-   7-chloro-1,2,3-benzotriazin-4(3H)-one;-   6-chloro-1,2,3-benzotriazin-4(3H)-one;-   5-chloro-1,2,3-benzotriazin-4(3H)-one;-   6,7-difluoro-1,2,3-benzotriazin-4(3H)-one;-   8-fluoro-1,2,3-benzotriazin-4(3H)-one;-   5-fluoro-1,2,3-benzotriazin-4(3H)-one;-   6-fluoro-1,2,3-benzotriazin-4(3H)-one;-   5-(6-methoxypyridin-3-yl)-1,2,3-benzotriazin-4(3H)-one;-   7-(6-methoxypyridin-3-yl)-1,2,3-benzotriazin-4(3H)-one; and-   7-(trifluoromethyl)-1,2,3-benzotriazin-4(3H)-one.

Synthesis of 5-tert-butyl-1H-isoindole-1,3(2H)-dione

The title compound was prepared following the procedure outlined in Can.J. Chem., Vol. 63, 121-128 (1985).

Mass (m/z): 204.12 (M⁺+1)

The following analogues of 5-tert-butyl-1H-isoindole-1,3(2H)-dione wereprepared analogously:

-   4-fluoro-1H-isoindole-1,3(2H)-dione; and-   5-chloro-1H-isoindole-1,3(2H)-dione.

Synthesis of (4-bromobenzyl)(triphenyl)phosphonium bromide

A mixture of 1-bromo-4-(bromomethyl)benzene (5 g) and triphenylphosphine(5.24 g) in xylene (20 mL) were heated to reflux for 18 hours. Thereaction mixture was cooled, filtered, washed with hexane, and driedunder vacuum to afford the title compound (8 g).

Mass (m/z): 433.9 (M⁺+1)

The following Wittig salts were prepared analogously:

-   [(4-bromo-2-thienyl)methyl]triphenyl phosphonium bromide;-   [(6-bromopyridin-3-yl)methyl](triphenyl)phosphonium bromide;-   (4-bromo-2-fluorobenzyl)(triphenyl)phosphonium bromide;-   4-tert-butylbenzyl(triphenyl)phosphonium bromide;-   triphenyl[4-(trifluoromethyl)benzyl]phosphonium bromide;-   benzyl(triphenyl)phosphonium bromide;-   (4-bromo-3-fluorobenzyl)(triphenyl)phosphonium bromide;-   (4-bromo-2-fluorobenzyl)(triphenyl)phosphonium bromide; and-   (4-chloro-3-fluorobenzyl)(triphenyl)phosphonium bromide.

Synthesis of 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid Step a:Synthesis of ethyl 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoate

In a dry round bottom flask, 1,2,3-benzotriazin-4(3H)-one (50 g), ethyl4-bromobutanoate (86.2 g) and potassium carbonate (141 g) were taken anddissolved in dimethylformamide (350 mL) and heated to 60° C. to 70° C.for 3 to 4 hours. After cooling to room temperature, water was added tothe reaction mixture and extracted with ethyl acetate. The combinedorganic layer was washed with water and brine and dried over anhydroussodium sulfate. Solvents were evaporated under reduced pressure and thecrude product was purified by silica gel flash column chromatographyover silica gel using 20% ethylacetate in hexane as eluant to afford thetitle compound (68 g).

Step b: Synthesis of 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoic acid

To a stirred solution of compound obtained from step a above (40 g), ina solvent mixture of tetrahydrofuran/methanol/water (3:1:1, 400 mL),lithium hydroxide monohydrate (6.43 g) was added at 0° C. under anitrogen atmosphere. The reaction mixture was stirred at 0° C. untilcompletion of hydrolysis. The solvents were evaporated, diluted withwater, and extracted with ethyl acetate. The aqueous layers wereacidified with saturated aqueous sodium hydrogen sulfate solution andextracted with ethyl acetate. The combined layers were washed with waterand brine and dried over anhydrous sodium sulfate. The solvents wereevaporated under reduced pressure to afford the title compound (28 g).

The following analogue of 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoicacid was prepared analogously:

-   3-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)propanoic acid.

Synthesis of3-{4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-4-oxobutyl}-1,2,3-benzotriazin-4(3H)-oneStep a: Synthesis of (2S)-2-amino-3-phenylpropan-1-ol

(Ref: J. Org. Chem., 58, 3568-3571 (1993)).

To a suspension of sodium borohydride (16.5 g) in dry tetrahydrofuran(600 mL), (L)-phenylalanine (30 g) was added at one portion. The flaskwas cooled to 0° C. under nitrogen atmosphere. Iodine (46.18 g) solutionin tetrahydrofuran (150 mL) was added slowly in drop-wise manner over 40minutes, resulting in vigorous evolution of H₂. After the completeaddition of iodine, the reaction mixture was heated to reflux for 18hours and cooled to room temperature. The reaction mixture was quenchedwith methanol until the reaction mixture became clear. Further, thesolution was stirred for 30 minutes at room temperature. The solventswere removed by rotary evaporation to obtain a white paste which wasdissolved by 20% aqueous potassium hydroxide (450 mL). The solution wasstirred for 4 hours and then dichloromethane was added. The organiclayers were separated and the aqueous layer was extracted withdichloromethane. The combined organic layers were washed with brine anddried over anhydrous sodium sulfate. The solvents were evaporated underreduced pressure to afford 32.5 g of (L)-phenylalaninol as a viscousliquid. The crude product was used as such for the next step.

Step b: Synthesis of (4S)-4-benzyl-1,3-thiazolidine-2-thione

(Ref: J. Org. Chem., 60(20), 6604-6607 (1995)).

To a solution of the compound obtained in step a above (32.5 g) in 1Naqueous potassium hydroxide (1 L), carbon disulphide (68 mL, 5.0equivalence) was added and the reaction mixture was refluxed for 16hours. After cooling to room temperature, the aqueous solution wasextracted with dichloromethane. The organic layer was washed with brine,dried over anhydrous sodium sulfate, and concentrated under reducedpressure. The crude product was purified by silica gel flash columnchromatography using 15% ethyl acetate in hexane to get the titlecompound (22.5 g).

Step c: Synthesis of (4S)-4-benzyl-1,3-thiazolidin-2-one

To a solution of (4S)-4-benzyl-1,3-thiazolidine-2-thione (38 g) indichloromethane (350 mL) cooled to 0° C., propylene oxide (12.7 mL) andtrifluoroacetic acid (14 mL) were added. After stirring the reactionmixture for 2 hours, the solvents were evaporated under reduced pressureto obtain a residue which was purified by column chromatography oversilica gel using 20% ethyl acetate in hexane as eluant to afford thetitle compound (0.9 g).

Mass (m/z): 194.18

Step d: Synthesis of3-{4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-4-oxobutyl}-1,2,3-benzotriazin-4(3H)-one

To a solution of the compound obtained from step c above (2.1 g) indichloromethane (25 mL) cooled to 0° C., 4-dimethylaminopridine (0.334g) and triethylamine (5.7 mL) were added. After stirring the reactionmixture for 10 minutes, 1-(3-dimethylaminopropyl)-3-ethylcarbodimidehydrochloride (3.9 g) and 4-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)butanoicacid (3 g) were added, and the reaction mixture was stirred at roomtemperature for 14 hours. Dichloromethane and water were added to thereaction mixture. The organic layer was separated, washed with water andbrine solution, and dried over anhydrous sodium sulphate. The solventwas evaporated under reduced pressure to obtain a residue which waspurified by column chromatography over silica gel using 25% ethylacetate in hexane as eluant to afford the title compound (4.4 g). Mass(m/z): 409.16

The following analogue of3-{4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-4-oxobutyl}-1,2,3-benzotriazin-4(3H)-onewas prepared analogously:

-   3-{3-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one

Example 1 Synthesis of(2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoicacid (Compound No. 1) Step a: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-D-arabinofuranose

D-Arabinose (200 g) and imidazole (199 g) were placed in a three-neckround bottom flask and connected to high vacuum for 30 minutes. Thevacuum was released under nitrogen atmosphere and dimethylformamide (1.8L) was added to the above mixture at room temperature followed bydrop-wise addition of t-butyldiphenylchlorosilane (443 mL) for 10minutes under a nitrogen atmosphere. The resulting mixture was stirredfor 16 hours at the same temperature. Dimethylformamide was evaporatedunder reduced pressure. The residue was taken up in ethyl acetate andwashed with water. The organic layer was dried over anhydrous sodiumsulphate. The solvent was evaporated under reduced pressure to obtain acrude residue which was purified by column chromatography over silicagel using 80% ethyl acetate in hexane as eluant to afford the titlecompound (273 g).

Mass (m/z): 389.37 (M⁺+1)

Step b: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-1,2-O-isopropylidene-β-D-arabinofuranose

To the solution of the compound obtained from step a above (273 g) inacetone (2.5 L), DL-camphorsulphonic acid (16 g) and anhydrous coppersulphate (346 g) were charged under a nitrogen atmosphere at roomtemperature. The reaction mixture was stirred for 16 hours at the sametemperature. A saturated solution of sodium bicarbonate (2 L) was addeddrop-wise until a basic pH was attained, and the reaction mixture wasfurther stirred for 2 hours at the same temperature. The resultingmixture was filtered using a Buchner funnel, and the residue was washedwith acetone. The filtrate was concentrated, dissolved in ethyl acetate,and washed with water. The organic layer was dried over anhydrous sodiumsulphate, filtered, and evaporated under reduced pressure to furnish thetitle compound (295 g).

Mass (m/z): 429.41 (M⁺+1)

Step c: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-1,2-O-isopropylidene-β-D-threo-pentofuranos-3-ulose

Oxalyl chloride (145 ml) and dichloromethane (1 L) were taken in a threeneck round bottom flask and cooled to −75° C. under a nitrogenatmosphere. Dimethylsulfoxide (212 mL) was added drop-wise to the abovesolution maintaining the reaction temperature at −70° C. The reactionmixture was stirred for 30 minutes at the same temperature, then asolution of the compound obtained from step b above (285 g) indichloromethane (1 L), was added slowly to the above mixture,maintaining the reaction temperature −70° C. After 20 minutes of theabove addition, triethylamine (560 mL) was added drop-wise at the sametemperature. Saturated solution of ammonium chloride in water (1.5 L)was then added after 30 minutes and the reaction temperature was allowedto rise to room temperature. The reaction mixture was extracted withdichloromethane. Organic extracts were dried over anhydrous sodiumsulphate, filtered, and evaporated under reduced pressure to afford thetitle compound (285 g).

Step d: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-ethoxy-2-oxoethylidene)-1,2-O-isopropylidene-β-D-arabinofuranose

To a suspension of sodium hydride (29.4 g, 60% in oil) intetrahydrofuran (1 L) at 0° C., triethyl phosphonoacetate (200 mL) wascharged. After 20 minutes, a solution of the compound obtained from stepc above (285 g) in tetrahydrofuran (2 L) was added drop-wise and thereaction mixture was stirred for 1 hour at the same temperature. Asaturated solution of ammonium chloride in water (1.5 L) was added tothe reaction mixture. The resulting mixture was extracted with ethylacetate. Combined extracts were dried over anhydrous sodium sulphate andevaporated under reduced pressure to yield a residue which was purifiedby column chromatography over silica gel using 15% ethyl acetate inhexane as eluant to afford the title compound (275 g).

Mass (m/z): 497.43 (M⁺+1)

Step e: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-ethoxy-2-oxoethyl)-1,2-O-isopropylidene-β-D-lyxofuranoseand5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-ethoxy-2-oxoethyl)-1,2-O-isopropylidene-α-L-ribofuranose

10% Palladium on charcoal (100 g) was added to the solution of thecompound obtained from step d above (275 g) in tetrahydrofuran (2 L) andmethanol (1 L) at room temperature and hydrogen was supplied at 50 psi(Paar apparatus) for 2 hours. The reaction mixture was filtered througha celite pad and the residue was washed with ethyl acetate. The filtratewas concentrated to afford a mixture of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-ethoxy-2-oxoethyl)-1,2-O-isopropylidene-β-D-lyxofuranoseand5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-ethoxy-2-oxoethyl)-1,2-O-isopropylidene-α-L-ribofuranose(275 g).

Mass (m/z): 499.42 (M⁺+1)

Step f: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-hydroxyethyl)-1,2-O-isopropylidene-β-D-lyxofuranoseand5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-hydroxyethyl)-1,2-O-isopropylidene-α-L-ribofuranose

To a suspension of lithium aluminum hydride (48 g) in tetrahydrofuran (1L), a solution of the compound obtained from step e above (275 g) intetrahydrofuran (1.5 L) was added at −50° C. The resulting mixture wasallowed to attain 0° C. The reaction mixture was stirred for 30 minutesat the same temperature and again cooled to −50° C. Ethyl acetate (2 L)was added slowly while maintaining −50° C. An aqueous solution ofammonium chloride (100 g) in water (2.5 L) was added at the sametemperature. The reaction mixture was slowly allowed to warm to roomtemperature, and the reaction mixture was stirred for 12 hours at thesame temperature. The reaction mixture was then filtered through acelite pad and the residue was washed with ethyl acetate. The organiclayer was dried over anhydrous sodium sulphate, filtered, concentratedunder reduced pressure, and the residue thus obtained was purified bycolumn chromatography over silica gel using 50% ethyl acetate in hexaneas eluant to afford the5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-hydroxyethyl)-1,2-O-isopropylidene-β-D-lyxofuranose(130 g) and5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-hydroxyethyl)-1,2-O-isopropylidene-α-L-ribofuranose(40.0 g).

Mass (m/z): 457.39 (M⁺+1)

Step g: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-1,2-O-isopropylidene-3-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-β-D-lyxofuranose

5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-hydroxyethyl)-1,2-O-isopropylidene-β-D-lyxofuranose(35 g), triphenylphosphine (30.8 g) and 1,2,3-benzotriazin-4(3H)-one(12.6 g) were dried in high vacuum in a round bottom flask for 10minutes. Then the vacuum was released under a nitrogen atmosphere andtetrahydrofuran (70 mL) was added to the above reaction mixture. Thereaction mixture was cooled to 0° C. and diisopropyl azodicarboxylate(17 mL) was added slowly. The reaction mixture was stirred for 30minutes at the same temperature, and then quenched with water andextracted with ethyl acetate. The organic layer was washed with waterand brine solution, dried over anhydrous sodium sulphate, andconcentrated to obtain a residue which was purified by columnchromatography over silica gel using 30% ethyl acetate in hexane aseluant to afford the title compound (50 g).

Mass (m/z): 586.05 (M⁺+1)

Step h: Synthesis of3-deoxy-1,2-O-isopropylidene-3-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-β-D-lyxofuranose

To a solution of the compound obtained from step g above (50 g) in drytetrahydrofuran (400 mL) at 0° C., tetra-butyl ammonium fluoride (170mL) was added. The resulting mixture was initially stirred at 0° C. for1 hour, and then at room temperature for 4 hours. The reaction mixturewas cooled to 0° C., quenched with saturated ammonium chloride, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous sodium sulphate and concentrated. Theresidue thus obtained was purified by column chromatography over silicagel using 80% ethyl acetate in hexane as eluant to furnish the titlecompound (22 g).

Mass (m/z): 369.98 (M⁺+23)

Step i: Synthesis of(5S)-3-deoxy-4,5-O-isopropylidene-3-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-D-arabino-pentodialdo-5,2-furanose

Oxalyl chloride (13.7 mL) and dichloromethane (300 mL) were taken in athree neck round bottom flask and cooled to −78° C. Dimethylsulfoxide(20.2 mL) was added drop-wise to the reaction mixture. The reactionmixture was warmed to −35° C. for 5 to 10 minutes and again cooled to−78° C. A solution of the compound obtained from step h above (22 g) indichloromethane (200 mL) was added slowly while maintaining the sametemperature. The reaction mixture was stirred for 45 minutes until thereaction temperature reached −35° C. The reaction mixture was againcooled to −78° C. and triethylamine (53 mL) was added. The reactionmixture was stirred for an additional 30 minutes, and the temperaturewas allowed to reach −35° C. The reaction mixture was quenched with asaturated solution of ammonium chloride and extracted withdichloromethane. The combined organic layers were washed with water andbrine solution, dried over anhydrous sodium sulphate, and concentratedto furnish the title compound (22 g).

Step j: Synthesis of3-(2-{(3aS,5R,6S,6aS)-5-[(E)-2-(4-bromophenyl)vinyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

To the suspension of sodium hydride (3.3 g, 60% in oil) intetrahydrofuran (50 mL) cooled to 0° C.,(4-bromobenzyl)triphenylphosphonium bromide (48.8 g) in tetrahydrofuran(100 mL) was added. A solution of the compound obtained from step iabove (22 g) in tetrahydrofuran (100 mL) was added drop-wise after 20minutes, and the reaction mixture was stirred for 1 hour at the sametemperature. The reaction mixture was quenched with water and extractedwith ethyl acetate. The organic layer was washed with water and brinesolution and dried over anhydrous sodium sulphate. The solvent wasevaporated under reduced pressure and the residue thus obtained waspurified by column chromatography using 30% ethyl acetate in hexane aseluant to furnish the title compound (24.5 g).

Mass (m/z): 498.84 (M⁺+1)

Step k: Synthesis of3-(2-{(3aS,5R,6S,6aS)-2,2-dimethyl-5-[(E)-2-(4-pyrimidin-5-ylphenyl)vinyl]tetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

A mixture of the compound obtained from step j above (0.35 g),pyrimidin-5-ylboronic acid (0.174 g),tetrakistriphenylphosphinepalladium (0) (0.081 g), and potassiumcarbonate (0.291 g) was dried under high vacuum for 10 minutes and drydimethylformamide (5 mL) was added at room temperature. The reactionmixture was heated at 120° C. for 2 hours, and then quenched with waterand extracted with ethyl acetate. The organic layer was washed withwater and brine solution and dried over anhydrous sodium sulphate. Thesolvent was evaporated under the reduced pressure to obtain a residuewhich was purified by column chromatography over silica gel using 40%ethyl acetate in hexane as eluant to afford the title compound (0.3 g).

Mass (m/z): 498.0 (M⁺+1)

Step l: Synthesis of3-(2-{(3aS,5R,6S,6aS)-2,2-dimethyl-5-[2-(4-pyrimidin-5-ylphenyl)ethyl]tetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

To the solution of the compound obtained from step k above (0.3 g) in asolvent mixture of tetrahydrofuran: methanol (10 mL, 1:1), 10% palladiumon charcoal (0.15 g) was added at room temperature and the reactionmixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paarapparatus. The reaction mixture was filtered through a celite pad andthe residue was washed with methanol. The filtrate was concentrated toafford the title compound (0.3 g).

Step m: Synthesis of3-(2-{(2R,3R,4S,5R)-4,5-dihydroxy-2-[2-(4-pyrimidin-5-ylphenyl)ethyl]tetrahydrofuran-3-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

Perchloric acid (0.2 mL) was added to a solution of the compoundobtained from step 1 above (0.3 g) in acetonitrile (4 mL) and water (0.2mL) at room temperature. The reaction mixture was heated to 55° C. for30 minutes. The reaction mixture was then quenched using sodiumbicarbonate solution. The solvents were evaporated under reducedpressure. The residue thus obtained was taken up in ethyl acetate andwater. The organic layer was separated and washed with water and brinesolution and dried over anhydrous sodium sulphate. The solvent wasconcentrated under reduced pressure to yield the title compound (0.25g).

Step n: Synthesis of(2S,3R)-3-(formyloxy)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoicacid

To a solution of the compound obtained from step m above (0.25 g) intert-butanol: tetrahydrofuran (5 mL:5 mL) at 0° C., a solution of sodiummetaperiodate (0.465 g in 5 mL of water) was added. The reaction mixturewas stirred for 2 hours at the same temperature and potassiumpermanganate (0.017 g) was added at 0° C. After stirring the reactionmixture for an additional 6 hours at room temperature, the reactionmixture was evaporated on a rotary evaporator. The residue was takeninto water and extracted with ethyl acetate. The organic layer waswashed with water and brine solution and dried over anhydrous sodiumsulphate. The solvent was evaporated under the reduced pressure toafford the title compound (0.25 g).

Step o: Synthesis of(2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoicacid

Potassium carbonate (0.081 g) was added to a solution of the compoundobtained from step n above (0.25 g) in methanol (5 mL) andtetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 3 hours. Solvents were evaporated and the residue wastaken into water and ethyl acetate. The organic layer was washed withwater and brine solution and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to obtain a residue whichwas purified by column chromatography over silica gel using 60% ethylacetate in hexane as eluant to afford the title compound (0.030 g).

Mass (m/z): 446.0 (M⁺+1).

¹HNMR (CD₃OD): δ 9.09 (s, 1H), 9.03 (s, 1H), 8.30 (d, 1H, J=8 Hz), 8.14(d, 1H, J=8 Hz), 8.05-8.03 (m, 1H), 7.89-7.87 (m, 1H), 7.61 (d, 2H, J=8Hz), 7.53-7.59 (m, 1H), 7.35 (d, 2H, J=8 Hz), 4.57-4.52 (m, 2H),3.79-3.77 (m, 1H), 2.89-2.87 (m, 1H), 2.69-2.67 (m, 1H), 2.47-2.46 (m,1H), 2.29-2.25 (m, 2H), 1.82-1.77 (m, 2H).

Example 1A Synthesis of(2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 86) Step a: Synthesis of3-(2-{(3aS,5R,6S,6aS)-5-[(E)-2-(4-bromophenyl)ethenyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

To the suspension of potassium t-butoxide (3.3 g, 60% in oil) indimethyl sulfoxide (50 mL) cooled to 0° C., 4-bromobenzyltriphenyl-phosphonium bromide (48.8 g) in dimethyl sulfoxide (100 mL)was added. After 20 minutes, the compound obtained from step i ofExample 1 above (22 g) was added in dimethyl sulfoxide (100 mL)drop-wise, and the reaction mixture was stirred for 1 hour at the sametemperature. The reaction mixture was quenched with water and extractedwith ethyl acetate. The organic layer was washed with water and brinesolution and dried over anhydrous sodium sulphate. The solvent wasevaporated under reduced pressure. Purification was performed on asilica gel column by using 30% ethyl acetate in hexane as eluent to getthe title compound (24.5 g).

Step b: Synthesis of3-{2-[(3aS,5R,6S,6aS)-5-{(E)-2-[4-(6-methoxypyridin-3-yl)phenyl]ethenyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]ethyl}-1,2,3-benzotriazin-4(3H)-one

A mixture of the compound obtained from step a above (12 g),2-methoxy-5-pyridine boronic acid (7.4 g),tetrakistriphenylphosphinepalladium (0) (2.8 g), and potassium carbonate(10 g) was dried under high vacuum for 10 minutes, and drydimethylformamide (60 ml) was added at room temperature. The reactionmixture was heated at 120° C. for 2 hours, and then quenched with waterand extracted with ethyl acetate. The organic layer was washed withwater and brine solution and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to obtain a residue whichwas purified by column chromatography over silica gel using 40% ethylacetate in hexane as eluant to afford the title compound (8.5 g).

Step c: Synthesis of3-{2-[(3aS,5R,6S,6aS)-5-{2-[4-(6-methoxypyridin-3-yl)phenyl]ethyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]ethyl}-1,2,3-benzotriazin-4(3H)-one

To the solution of the compound obtained from step b above (8.5 g) in asolvent mixture of tetrahydrofuran:methanol (60 mL:40 mL), 10% palladiumon charcoal (4 g) was added at room temperature, and the reactionmixture was hydrogenated with hydrogen at 35 psi for 4 hours in a Paarapparatus. The reaction mixture was filtered through a celite pad andthe residue was washed with methanol. The filtrate was concentrated toafford the title compound (8.1 g).

Step d: Synthesis of3-{2-[(2R,3R,4S,5R)-4,5-dihydroxy-2-{2-[4-(6-methoxypyridin-3-yl)phenyl]ethyl}tetrahydrofuran-3-yl]ethyl}-1,2,3-benzotriazin-4(3H)-one

Perchloric acid (4.8 mL) was added to a solution of the compoundobtained from step c above (8.1 g) in acetonitrile (50 mL) and water (8mL) at room temperature. The reaction mixture was heated to 55° C. for30 minutes. The reaction mixture was then quenched using sodiumbicarbonate solution. The solvents were evaporated under reducedpressure. The residue thus obtained was taken up in ethyl acetate andwater. The organic layer was separated, washed with water and brinesolution, and dried over anhydrous sodium sulphate. The solvent wasconcentrated under reduced pressure to yield the title compound (8 g).

Step e: Synthesis of(2S,3R)-3-(formyloxy)-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid

To a solution of the compound obtained from step d above (8 g) intert-butanol:tetrahydrofuran (40 mL:40 mL) at 0° C., a solution ofsodium metaperiodate (14 g in 40 mL of water) was added. The reactionmixture was stirred for 2 hours at the same temperature, and potassiumpermangnate (518 mg) was added at 0° C. After stirring the reactionmixture for an additional 6 hours at room temperature, the reactionmixture was evaporated on a rotary evaporator. The residue was takeninto water and extracted with ethyl acetate. The organic layer waswashed with water and brine solution and dried over anhydrous sodiumsulphate. The solvent was evaporated under the reduced pressure, toafford the title compound (8 g).

Step f: Synthesis of(2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid

Potassium carbonate (2.3 g) was added to a solution of the compoundobtained from step e above (8 g) in methanol (40 mL) and tetrahydrofuran(30 mL) at 0° C. The reaction mixture was stirred at room temperaturefor 3 hours. The solvents were evaporated, and the residue was takeninto water and ethyl acetate. The organic layer was washed with waterand brine solution and dried over anhydrous sodium sulphate. The solventwas evaporated under reduced pressure to obtain a residue which waspurified by column chromatography over silica gel using 60% ethylacetate in hexane as eluant to afford the title compound (3 g).

Mass (m/z): 474.87 (M⁺+1); ¹H NMR (400 MHz, MeOD): δ 8.32-8.30 (2H, m),8.16-8.14 (1H, m), 8.04-8.03 (1H, m), 7.92-7.88 (2H, m), 7.46 (2H, d,J=8 Hz), 7.24 (2H, m, J=8 Hz), 6.86 (1H, d, J=8 Hz), 4.57-4.53 (2H, m),3.93 (3H, s), 3.78-3.83 (1H, m), 2.83-2.80 (1H, m), 2.63-2.60 (1H, m),2.52-2.49 (1H, m), 2.32-2.28 (2H, m), 1.80-1.76 (2H, m).

Example 1B Synthesis of(2S,3R)-3-hydroxy-5-[4-(6-hydroxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 226)

To a solution of the compound obtained from Example 1A above (0.2 g) indry toluene (5 mL), cooled to 78° C., boron tribromide (0.5 mL) wasadded and the contents were stirred at room temperature for 4 hours.Ethyl acetate and water were added to the reaction mixture. The organiclayer was separated, washed with water and brine, and dried overanhydrous sodium sulfate. The solvent was evaporated to obtain a residuewhich was purified by preparatory thin layer chromatography (2 mmthickness) using 15% methanol in dichloromethane as eluent to get thetitle compound (60 mg).

Mass (m/z): 461.23 (M⁺+1); ¹HNMR (CD₃OD): 8.30 (d, 1H, J=8 Hz), 8.15 (d,1H, J=8 Hz), 8.06-8.01 (m, 2H), 7.88 (t, 1H, J=8 Hz), 7.79-7.76 (m, 1H),7.43 (d, 2H, J=12 Hz), 7.25 (d, 2H, J=12 Hz), 6.75 (d, 1H, J=12 Hz),4.58-4.51 (m, 2H), 3.82-3.76 (m, 1H), 2.88-2.78 (m, 1H), 2.66-2.57 (m,1H), 2.54-2.47 (m, 1H), 2.33-2.25 (m, 2H), 1.84-1.70 (m, 2H).

Example 1C Synthesis of(2S,3R)-3-(acetyloxy)-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 229)

Diisopropyl azodicarboxylate (63 mg) was added to a solution of thecompound obtained from Example 1A above (100 mg), tri-n-butylphosphine(93 mg), and acetic acid (1 mL) in dry tetrahydrofuran (3 mL) at 0° C.The reaction mixture was stirred for 1 hour and concentrated. Theresidue was taken in ethyl acetate, and washed with water and brine. Theorganic layer was concentrated to get an oily residue which was purifiedon preparative thin layer chromatography (2 mm thickness) using 10%methanol in dichloromethane to get the title compound (80 mg).

Mass (m/z): 517.06 (M⁺+1); ¹HNMR: δ 8.37 (m, 2H), 8.15 (d, 1H, J=8 Hz),7.97-7.93 (m, 1H), 7.82-7.80 (m, 1H), 7.41 (d, 2H, J=8 Hz), 7.20 (d, 2H,J=8 Hz), 6.83 (d, 1H, J=8 Hz), 5.28-5.27 (m, 1H), 4.56-4.58 (m, 2H),4.01 (s, 3H), 2.85-2.80 (m, 1H), 2.55-2.75 (m, 2H), 2.31-2.29 (m, 2H),2.25-2.10 (m, 2H), 2.063 (s, 3H).

Example 1D Synthesis of(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoicacid (Compound No. 88) Step a: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,2-O-(1-methylethylidene)-β-D-lyxofuranose

5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-(2-hydroxyethyl)-1,2-O-isopropylidene-β-D-lyxofuranose(14 g), triphenylphosphine (12 g), and phthalimide (5 g) were dried in ahigh vacuum in a round bottom flask for 10 minutes. Then the vacuum wasreleased under a nitrogen atmosphere, and tetrahydrofuran (100 mL) wasadded to the above reaction mixture. The reaction mixture was cooled to0° C. and diethyl azodicarboxylate (7.8 mL) was added slowly. Thereaction mixture was stirred for 30 minutes at the same temperature, andthen quenched with water and extracted with ethyl acetate. The organiclayer was washed with water and brine solution, dried over anhydroussodium sulphate, and concentrated to obtain a residue which was purifiedby column chromatography over silica gel using 30% ethyl acetate inhexane as eluant to afford the title compound (11 g).

Step b: Synthesis of3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,2-O-(1-methylethylidene)-β-D-lyxofuranose

To a solution of the compound obtained from step a above (11 g) in drytetrahydrofuran (50 mL) at 0° C., tetra-butyl ammonium fluoride (41.36mL) was added. The resulting mixture was initially stirred at 0° C. for1 hour, and then at room temperature for 4 hours. The reaction mixturewas cooled to 0° C., quenched with saturated ammonium chloride, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous sodium sulphate, and concentrated. Theresidue thus obtained was purified by column chromatography over silicagel using 80% ethyl acetate in hexane as eluant to furnish the titlecompound (5 g).

Step c: Synthesis of(5S)-3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4,5-O-(1-methylethylidene)-D-arabino-pentodialdo-5,2-furanose

Oxalyl chloride (4.5 mL) and dichloromethane (20 mL) were taken in athree neck round bottom flask and cooled to −78° C. Dimethylsulfoxide(6.6 mL) was added drop-wise to the reaction mixture. The reactionmixture was warmed to −35° C. for 5 to 10 minutes and again cooled to−78° C. A solution of the compound obtained from step b above (7.2 g) indichloromethane (20 mL) was added slowly while maintaining the sametemperature. The reaction mixture was stirred for 45 minutes until thereaction temperature reached −35° C. The reaction mixture was againcooled to −78° C. and triethylamine (17.3 mL) was added. The reactionmixture was stirred for an additional 30 minutes, and the temperaturewas allowed to reach −35° C. The reaction mixture was quenched withsaturated solution of ammonium chloride, and extracted withdichloromethane. The combined organic layers were washed with water andbrine solution, dried over anhydrous sodium sulphate, and concentratedto furnish the title compound (7.3 g).

Step d: Synthesis of2-(2-{(3aS,5R,6S,6aS)-5-[(E)-2-(4-bromophenyl)ethenyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1H-isoindole-1,3(2H)-dione

To a suspension of potassium t-butoxide (2.3 g) in dimethyl sulfoxide(30 ml) cooled to 0° C., (4-bromobenzyl)triphenylphosphonium bromide(12.2 g) in dimethyl sulfoxide (20 mL) was added. After 20 minutes, asolution of compound obtained from step c above (4.1 g) in dimethylsulfoxide (10 mL) was added drop-wise, and the reaction mixture wasstirred for 1 hour at the same temperature. The reaction mixture wasquenched with water, and extracted with ethyl acetate. The organic layerwas washed with water and brine solution and dried over anhydrous sodiumsulphate. The solvent was evaporated under reduced pressure.Purification was performed on silica gel column by using 40% ethylacetate in hexane as eluant to furnish the title compound (4 g).

Step e: Synthesis of2-{2-[(3aS,5R,6S,6aS)-5-{(E)-2-[4-(6-methoxypyridin-3-yl)phenyl]ethenyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]ethyl}-1H-isoindole-1,3(2H)-dione

A mixture of the compound obtained from step d above (1 g),2-methoxy-5-pyridine boronic acid (0.614 g),tetrakistriphenylphosphinepalladium (0) (0.115 g), and potassiumcarbonate (0.832 g) was dried under high vacuum for 10 minutes, and drydimethylformamide (8 mL) was added at room temperature. The reactionmixture was heated at 120° C. for 2 hours, and then quenched with waterand extracted with ethyl acetate. The organic layer was washed withwater and brine solution, and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to obtain a residue whichwas purified by column chromatography over silica gel using 30% ethylacetate in hexane as eluant to afford the title compound (0.62 g).

Step f: Synthesis of2-{2-[(3aS,5R,6S,6aS)-5-{2-[4-(6-methoxypyridin-3-yl)phenyl]ethyl}-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl]ethyl}-1H-isoindole-1,3(2H)-dione

To a solution of the compound obtained from step e above (0.6 g) inmethanol (10 mL), 10% palladium on charcoal (0.05 g) was added at roomtemperature and the reaction mixture was hydrogenated with hydrogen at35 psi for 4 hours in a Paar apparatus. The reaction mixture wasfiltered through a celite pad and the residue was washed with methanol.The filtrate was concentrated to afford the title compound (0.56 g).

Step g: Synthesis of2-{2-[(2R,3R,4S,5R)-4,5-dihydroxy-2-{2-[4-(6-methoxypyridin-3-yl)phenyl]ethyl}tetrahydrofuran-3-yl]ethyl}-1H-isoindole-1,3(2H)-dione

Perchloric acid (0.4 mL) was added to a solution of the compoundobtained from step f above (0.5 g) in acetonitrile (4 mL) and water (0.8mL) at room temperature. The reaction mixture was heated to 55° C. for30 minutes. The reaction mixture was then quenched using sodiumbicarbonate solution. The solvents were evaporated under reducedpressure. The residue thus obtained was taken up in ethyl acetate andwater. The organic layer was separated, washed with water and brinesolution, and dried over anhydrous sodium sulphate. The solvent wasconcentrated under reduced pressure to yield the title compound (0.51g).

Step h: Synthesis of(1R,2S)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-formyl-1-{2-[4-(6-methoxypyridin-3-yl)phenyl]ethyl}butylformate

To a solution of the compound obtained from step g above (0.56 g) inmethanol (4 mL) at 0° C., a solution of sodium metaperiodate (0.736 g in1 mL of water) was added. The reaction mixture was stirred for 2 hoursat the same temperature. After stirring the reaction mixture for anadditional 1 hour at room temperature, the reaction mixture wasevaporated on a rotary evaporator. The residue was taken into water andextracted with ethyl acetate. The organic layer was washed with waterand brine solution, and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to obtain the titlecompound (0.54 g).

Step i: Synthesis of(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-(formyloxy)-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoicacid

The compound obtained in step h (0.54 g) was taken in acetonitrile (6mL) and water (1 mL). To this solution, sodium dihydrogen phosphate(0.054 g) was added. The reaction mixture was cooled to 0° C. andhydrogen peroxide (1 mL) and sodium chlorite (0.208 g) were added. Afterstirring the reaction mixture for an additional 1 hour, the solventswere evaporated on a rotary evaporator; the residue was taken into waterand extracted with ethyl acetate. The organic layer was washed withwater and brine solution, and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to get the title compound(0.5 g).

Step j: Synthesis of(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoicacid

Potassium carbonate (0.165 g) was added to a solution of the compoundobtained from step i above (0.4 g) in methanol (6 mL) at 0° C. Thereaction mixture was stirred at room temperature for 3 hours. Thesolvents were evaporated, and the residue was taken into water and ethylacetate. The organic layer was washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was evaporated underreduced pressure to obtain a residue which was purified with preparatoryTLC using 7% methanol in ethyl acetate as eluent to get the titlecompound (0.13 gm).

Mass (m/z): 474.88 (M⁺+1); ¹HNMR (CDCl₃):— δ 8.35 (s, 1H), 7.83-7.81 (m,2H), 7.77-7.69 (m, 3H), 7.42 (d, 2H, J=3 Hz), 7.25 (d, 2H, J=6 Hz), 6.80(d, 1H, J=6 Hz), 3.97 (s, 3H), 3.87-3.78 (m, 3H), 2.89 (m, 1H), 2.69 (m,1H), 2.57 (m, 1H), 2.15-1.98 (m, 2H), 1.84-1.79 (m, 2H).

Example 1E Synthesis of(2S,3R)-5-(2′,4′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid (Compound No. 97) Step a: Synthesis of2-(2-{(3aS,5R,6S,6aS)-5-[(E)-2-(3′,5′-difluorobiphenyl-4-yl)ethenyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1H-isoindole-1,3(2H)-dione

A mixture of the compound obtained from step d of Example 1D above (0.2g), 3,5-difluorophenyl boronic acid (0.135 g),tetrakistriphenylphosphinepalladium (0) (0.023 g), and potassiumcarbonate (0.2 g) was dried under high vacuum for 10 minutes and drydimethylformamide (3 mL) was added at room temperature. The reactionmixture was heated at 120° C. for 2 hours, and then quenched with waterand extracted with ethyl acetate. The organic layer was washed withwater and brine solution, and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to obtain a residue whichwas purified by column chromatography over silica gel using 30% ethylacetate in hexane as eluant to afford the title compound (0.205 g).

Step b: Synthesis of2-(2-{(3aS,5R,6S,6aS)-5-[2-(3′,5′-difluorobiphenyl-4-yl)ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1H-isoindole-1,3(2H)-dione

To the solution of the compound obtained from step a above (0.2 g) intetrahydrofuran (10 mL), 10% palladium on charcoal (0.1 g) was added atroom temperature, and the reaction mixture was hydrogenated withhydrogen at 35 psi for 4 hours in a Paar apparatus. The reaction mixturewas filtered through a celite pad, and the residue was washed withmethanol. The filtrate was concentrated to afford the title compound(0.2 g).

Step c: Synthesis of2-(2-{(2R,3R,4S,5R)-2-[2-(3′,5′-difluorobiphenyl-4-yl)ethyl]-4,5-dihydroxytetrahydrofuran-3-yl}ethyl)-1H-isoindole-1,3(2H)-dione

Perchloric acid (0.3 mL) was added to a solution of the compoundobtained from step b above (0.2 g) in acetonitrile (6 mL) and water (2mL) at room temperature. The reaction mixture was heated to 55° C. for30 minutes. The reaction mixture was then quenched using sodiumbicarbonate solution. The solvents were evaporated under reducedpressure. The residue thus obtained was taken up in ethyl acetate andwater. The organic layer was separated and washed with water and brinesolution, and dried over anhydrous sodium sulphate. The solvent wasconcentrated under reduced pressure to yield the title compound (0.15g).

Step d: Synthesis of(1R,2S)-1-[2-(3′,5′-difluorobiphenyl-4-yl)ethyl]-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-formylbutylformate

To a solution of the compound obtained from step c above (0.15 g) inmethanol (6 mL) at 0° C., a solution of sodium metaperiodate (0.15 g in1 mL of water) was added. The reaction mixture was stirred for 2 hoursat the same temperature. After stirring the reaction mixture for anadditional 1 hour at room temperature, the reaction mixture wasevaporated on a rotary evaporator. The residue was taken into water andextracted with ethyl acetate. The organic layer was washed with waterand brine solution, and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to obtain the titlecompound (0.12 g).

Step e: Synthesis of(2S,3R)-5-(3′,5′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-(formyloxy)pentanoicacid

The compound obtained from step d above (0.12 g) was taken inacetonitrile (6 mL) and water (1 mL). To this solution, sodiumdihydrogen phosphate (0.05 g) was added. The reaction mixture was cooledto 0° C., and hydrogen peroxide (0.5 mL) and sodium chlorite (0.15 g)were added. After stirring the reaction mixture for an additional 1hour, the solvents were evaporated on a rotary evaporator and theresidue was taken into water and extracted with ethyl acetate. Theorganic layer was washed with water and brine solution, and dried overanhydrous sodium sulphate. The solvent was evaporated under reducedpressure, to get the title compound (0.12 g).

Step f: Synthesis of(2S,3R)-5-(3′,5′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid

Potassium carbonate (0.06 g) was added to a solution of the compoundobtained from step e above (0.12 g) in methanol (10 mL) at 0° C. Thereaction mixture was stirred at room temperature for 3 hours. Thesolvents were evaporated, and the residue was taken into water and ethylacetate. The organic layer was washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was evaporated underreduced pressure to obtain a residue which was purified with preparatorythin layer chromatography using 10% methanol in ethyl acetate as eluentto get the title compound (0.025 gm).

Mass (m/z): 480.13 (M⁺+1); ¹HNMR (CD₃OD): δ 7.48-7.76 (m, 4H), 7.47-7.37(m, 3H), 7.25-7.23 (d, 2H), 7.03-6.98 (m, 2H), 3.78-3.72 (m, 3H),2.85-2.81 (m 1H), 2.65-2.63 (m, 1H), 2.42-2.40 (m, 1H), 2.10-2.05 (m,2H), 1.79-1.75 (m, 2H).

Example 2 Synthesis of(2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-phenylpentanoicacid (Compound No. 82) Step a: Synthesis of3-{2-[(3aS,5R,6S,6aS)-2,2-dimethyl-5-(2-phenylethyl)tetrahydrofuro[2,3-d][1,3]dioxol-6-yl]ethyl}-1,2,3-benzotriazin-4(3H)-one

To the solution of the compound obtained from step j of Example 1 (0.3g) in a solvent mixture of tetrahydrofuran:methanol (10 mL:10 mL)palladium/carbon (0.2 g, 10%) was added at room temperature, and thereaction mixture was hydrogenated at 35 psi for 4 hours in a Paarapparatus. The reaction mixture was filtered through a celite pad andthe residue was washed with methanol. The filtrate was concentrated toafford the title compound (0.3 g).

Mass (m/z): 421 (M⁺)

Step b: Synthesis of3-{2-[(2R,3R,4S,5R)-4,5-dihydroxy-2-(2-phenylethyl)tetrahydrofuran-3-yl]ethyl}-1,2,3-benzotriazin-4(3H)-one

Perchloric acid (0.2 mL) was added to a solution of the compoundobtained from step a above (0.3 g) in acetonitrile (4 mL) and water (0.3mL) at room temperature. The reaction mixture was heated to 55° C. for30 minutes. The reaction mixture was then quenched using a sodiumbicarbonate solution. The solvents were evaporated at reduced pressure.The residue thus obtained was taken up in ethyl acetate and water. Theorganic layer was separated, washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was concentrated underreduced pressure to yield the title compound (0.3 g).

Step c: Synthesis of(2S,3R)-3-(formyloxy)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-phenylpentanoicacid

To a solution of the compound obtained from step b above (0.3 g) intert-butanol:tetrahydrofuran (3 mL:3 mL) at 0° C., a solution of sodiummetaperiodate (0.673 g in 3 mL of water) was added. The reaction mixturewas stirred for 2 hours at the same temperature and potassiumpermanganate (0.025 g) was added at 0° C. After stirring the reactionmixture for an additional 6 hours at room temperature, the reactionmixture was evaporated and the residue was taken into water andextracted with ethyl acetate. The organic layer was washed with waterand brine solution, and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure, to afford the titlecompound (0.3 g).

Step d: Synthesis of(2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-phenylpentanoicacid

Potassium carbonate (0.11 g) was added to a solution of the compoundobtained from step c above (0.3 g) in methanol (4 mL) andtetrahydrofuran (4 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 3 hours. The solvents were evaporated, and the residuewas taken into water and ethyl acetate. The organic layer was washedwith water and brine solution, and dried over anhydrous sodium sulphate.The solvent was evaporated under reduced pressure to obtain a residuewhich was purified by column chromatography over silica gel using 10%methanol in dichloromethane as eluant to afford the title compound(0.020 g).

Mass (m/z): 368.0 (M⁺+1); ¹HNMR (CD₃OD): δ 8.31 (d, 1H, J=8 Hz), 8.15(d, 1H, J=8 Hz), 8.06-8.02 (m, 1H), 7.91-7.89 (m, 2H), 7.62 (d, 2H, J=8Hz), 7.36 (d, 1H, J=8 Hz), 7.21-7.07 (m, 1H), 4.57-4.52 (m, 2H),3.78-3.76 (m, 1H), 2.76-2.75 (m, 1H), 2.57-2.49 (m, 2H), 2.29-2.27 (m,2H), 1.74-1.71 (m, 2H).

Example 3 Synthesis of(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4(trifluoromethyl)phenyl]pentanoicacid (Compound No. 84) Step a: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,2-O-isopropylidene-β-D-lyxofuranose

A mixture of the compound obtained from step f of Example 1 (0.14 g),triphenylphosphine (0.080 g), and pthalimide (0.045 g) was taken in around bottom flask and dried in high vacuum for 10 minutes. The vacuumwas released under a nitrogen atmosphere and tetrahydrofuran (5 mL) wasadded to the reaction mixture. The reaction mixture was cooled to 0° C.and diethyl azodicarboxylate (0.1 mL) was added slowly. The reactionmixture was stirred for 30 minutes at the same temperature, and thenquenched with water and extracted with ethyl acetate. The organic layerwas washed with water and brine solution, dried over anhydrous sodiumsulphate, and concentrated. The residue thus obtained was purified bycolumn chromatography over silica gel using 30% ethyl acetate in hexaneas eluant to afford the title compound (0.11 g).

Mass (m/z): 608 (M⁺+23)

Step b: Synthesis of3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,2-O-isopropylidene-β-D-lyxofuranose

To a solution of the compound obtained from step a above (0.060 g) indry tetrahydrofuran (2 mL) at 0° C., tetra-butyl ammonium fluoride (0.2mL) was added. The resulting mixture was initially stirred at 0° C. for1 hour, and then at room temperature for 4 hours. The reaction mixturewas cooled to 0° C., quenched with saturated ammonium chloride, andextracted with ethyl acetate. The organic layer was washed with waterand brine, dried over anhydrous sodium sulphate, and concentrated. Theresidue thus obtained was purified by column chromatography over silicagel using 60% ethyl acetate in hexane as eluant to furnish the titlecompound (0.4 g).

Step c: Synthesis of(5S)-3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4,5-O-isopropylidene-D-arabino-pentodialdo-5,2-furanose

In a three-neck round bottom flask, oxalyl chloride (0.6 mL) anddichloromethane (20 mL) were placed and cooled to −78° C.Dimethylsulfoxide (1 mL) was added drop-wise to the reaction mixture.The reaction mixture was warmed to −35° C. for 5 to 10 minutes, andagain cooled to −78° C. A solution of the compound obtained from step babove (1 g) in dichloromethane (5 mL) was added slowly while maintainingthe same temperature. The reaction mixture was stirred for 45 minutesuntil the reaction temperature reached −35° C. The reaction mixture wasagain cooled to −78° C., and triethylamine (2.4 mL) was added. Thereaction mixture was stirred for an additional 30 minutes and thetemperature was allowed to reach −35° C. The reaction mixture wasquenched with a saturated solution of ammonium chloride, and extractedwith dichloromethane. The combined organic layer was washed with waterand brine solution, dried over anhydrous sodium sulphate, andconcentrated to furnish the title compound (1.0 g).

Step d: Synthesis of2-{2-[(3aS,5R,6S,6aS)-2,2-dimethyl-5-{(E)-2-[4-(trifluoromethyl)phenyl]vinyl}tetrahydrofuro[2,3-d][1,3]dioxol-6-yl]ethyl}-1H-isoindole-1,3(2H)-dione

To a suspension of triphenyl[4-(trifluoromethyl)benzyl]phosphoniumbromide (0.795 g) in dimethylsulphoxide (5 mL), potassium tert-butoxide(0.292 g) was added. A solution of the compound obtained from step cabove (0.5 g) in tetrahydrofuran (7 mL) was added drop-wise after 20minutes, and the reaction mixture was stirred for 1 hour at the sametemperature. The reaction mixture was quenched with water, and extractedwith ethyl acetate. The organic layer was washed with water and brinesolution and dried over anhydrous sodium sulphate. The solvent wasevaporated under reduced pressure and the residue thus obtained waspurified by column chromatography using 30% ethyl acetate in hexane aseluant to furnish the title compound (0.25 g).

Mass (m/z): 487 (M⁺)

Step e: Synthesis of2-{2-[(3aS,5R,6S,6aS)-2,2-dimethyl-5-{2-[4-(trifluoromethyl)phenyl]ethyl}tetrahydrofuro[2,3-d][1,3]dioxol-6-yl]ethyl}-1H-isoindole-1,3(2H)-dione

10% Palladium on charcoal (0.2 g) was added to the solution of compoundobtained from step d above (0.25 g) in ethyl acetate (20 mL) at roomtemperature, and the reaction mixture was hydrogenated at 50 psi for 4hours in a Paar apparatus. The reaction mixture was filtered through acelite pad, and the residue was washed with methanol. The filtrate wasconcentrated to afford the title compound (0.225 g).

Step f: Synthesis of2-{2-[(2R,3R,4S,5R)-4,5-dihydroxy-2-{2-[4-(trifluoromethyl)phenyl]ethyl}tetrahydrofuran-3-yl]ethyl}-1H-isoindole-1,3(2H)-dione

Perchloric acid (0.2 mL) was added to a solution of the compoundobtained from step e above (0.225 g) in acetonitrile (4 mL), water (1mL), and tetrahydrofuran (0.5 mL) at room temperature. The reactionmixture was heated to 55° C. for 30 minutes. The reaction mixture wasthen quenched using a sodium bicarbonate solution. The solvents wereevaporated at reduced pressure. The residue thus obtained was taken inethyl acetate and water. The organic layer was separated, washed withwater and brine solution, and dried over anhydrous sodium sulphate. Thesolvent was concentrated under reduced pressure to yield the titlecompound (0.22 g).

Step g: Synthesis of(1R,2S)-4-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-2-formyl-1-{2-[4-(trifluoromethyl)phenyl]ethyl}butylformate

A solution of sodium metaperiodate (0.313 g in 1 mL of water) was addedto a solution of the compound obtained from step f above (0.22 g) inmethanol:tetrahydrofuran (3 mL:1 mL) at 0° C. The reaction mixture wasstirred for 2 hours at same temperature. After stirring the reactionmixture for an additional 6 hours at room temperature, the reactionmixture was evaporated on a rotary evaporator, and the residue was takeninto water and extracted with ethyl acetate. The organic layer waswashed with water and brine solution, and dried over anhydrous sodiumsulphate. The solvent was evaporated under reduced pressure to affordthe title compound (0.22 g).

Step h: Synthesis of(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-(formyloxy)-5-[4-(trifluoromethyl)phenyl]pentanoicacid

To a solution of the compound obtained from step g above (0.22 g) in asolvent mixture of acetonitrile:water (3 mL:1 mL) at 0° C., sodiumdihydrogenphosphate (0.021 g), sodium chlorite (0.081 g) and hydrogenperoxide (1 mL, 30% in water) were added. The reaction mixture wasstirred for 2 hours at room temperature. The solvents were evaporatedunder reduced pressure to obtain a residue. Ethyl acetate and water wereadded to the resulting residue. The organic layer was separated, washedwith water and brine, and dried over anhydrous sodium sulphate. Thesolvent was evaporated under reduced pressure to afford the titlecompound (0.2 g).

Step i: Synthesis of(2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(trifluoromethyl)phenyl]pentanoicacid

Potassium carbonate (0.178 g) was added to a solution of the compoundobtained from step h above (0.2 g) in methanol (7 mL) at 0° C. Thereaction mixture was stirred at room temperature for 3 hours. Thesolvents were evaporated, and the residue was taken into water and ethylacetate. The organic layer was washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was evaporated underreduced pressure to obtain a residue which was purified by columnchromatography over silica gel using 10% methanol in dichloromethane aseluant to afford the title compound (0.090 g).

Mass (m/z): 458.0 (M⁺+23)

¹HNMR (CD₃OD): δ 7.83 (q, 2H, J=3.1 Hz), 7.71 (t, 2H, J=3.2 Hz), 7.51(d, 2H, J=7.6 Hz), 7.28 (d, 2H, J=7.9 Hz), 3.95-3.76 (m, 3H), 2.93-2.55(m, 3H), 2.14-1.75 (m, 4H).

Example 4 Synthesis of(2R,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid (Compound No. 89) Step a: Synthesis of1,2:5,6-Di-O-isopropyliden-α-D-ribo-3-hexulo-furanose

Oxalyl chloride (25.16 mL) and dichloromethane (200 mL) were taken in athree-neck round bottom flask and cooled to −75° C. under a nitrogenatmosphere. Then dimethylsulfoxide (27.3 mL) was added drop-wise slowlymaintaining the temperature at −70° C. The reaction mixture was stirredfor 30 minutes at the same temperature, and then diacetone-α-D-glucose(50 g) in dichloromethane (500 mL) was charged slowly, maintaining thetemperature at −70° C. After 20 minutes, triethylamine (80 mL) was addeddrop-wise to the above mixture at the same temperature. A saturatedsolution of ammonium chloride in water (500 mL) was charged to thereaction mixture after 30 minutes, and the temperature was allowed torise to room temperature. The reaction mixture was extracted withdichloromethane. The organic layer was dried over anhydrous sodiumsulphate. The solvent was evaporated under reduced pressure to affordthe title compound (45 g).

Step b: Synthesis of1,2:5,6-Di-O-isopropylidene-3-deoxy-3-(2-ethoxy-2-oxoethylidene)-α-D-ribo-hexofuranose

To a suspension of sodium hydride (0.155 g, 60% in oil) intetrahydrofuran (5 mL), triethyl phosphonoacetate (1.55 mL) was chargedat 0° C. After 20 minutes, a solution of the compound obtained from stepa above (1 g) in tetrahydrofuran (3 mL) was added drop-wise and thereaction mixture was stirred for 1 hour at the same temperature. Asaturated solution of ammonium chloride was added to the reactionmixture. The resulting mixture was extracted with ethyl acetate. Thecombined extracts were dried over anhydrous sodium sulphate, andevaporated under reduced pressure to yield a residue which was purifiedby column chromatography over silica gel using 30% ethyl acetate inhexane as eluant to afford the title compound (1.3 g).

Mass (m/z): 351.1 (M⁺+23)

Step c: Synthesis of1,2:5,6-Di-O-isopropylidene-3-deoxy-3-(2-ethoxy-2-oxoethyl)-α-D-allofuranose

10% Palladium on charcoal (0.05 g) was added to the solution of thecompound obtained from step b above (0.15 g) in ethyl acetate (10 mL) atroom temperature, and hydrogen was supplied at 50 psi for 4 hours. Thereaction mixture was filtered through a celite pad and the residue waswashed with ethyl acetate. The filtrate was concentrated to afford thetitle compound (0.12 g).

Mass (m/z): 353.2 (M⁺+1).

Step d: Synthesis of3-deoxy-3-(2-ethoxy-2-oxoethyl)-1,2-O-isopropylidene-α-D-allofuranose

30% Perchloric acid (4 mL) was added to a solution of the compoundobtained from step c above (2.0 g) in tetrahydrofuran (20 mL) at −5° C.to 0° C. The reaction mixture was stirred for 5 hours at −5° C. to 0° C.and then quenched with a saturated solution of sodium bicarbonate (20mL). The solvents were evaporated, and ethyl acetate and water wereadded to the resulting residue. The organic layer was separated, washedwith brine, dried over anhydrous sodium sulphate, and concentrated toafford the title compound (1.5 g).

Mass (m/z): 313.2 (M⁺+1)

Step e: Synthesis of3-deoxy-3-(2-ethoxy-2-oxoethyl)-1,2-O-isopropylidene-α-D-ribo-pentodialdo-1,4-furanose

To a solution of the compound obtained from step d above (1.5 g) inmethanol (15 mL), an aqueous solution of sodium periodate (1.65 g in 10mL of water) was added at 0° C. The reaction mixture was stirred for 3hours and brought from 0° C. to room temperature. The solvents wereevaporated. Ethyl acetate and water were added to the residue. Theorganic layer was separated, washed with brine, dried over anhydroussodium sulphate, and concentrated to afford the title compound (0.9 g).

Mass (m/z): 259.2 (M⁺+1)

Step f: Synthesis of ethyl{(3aR,5R,6R,6aR)-5-[(E)-2-(4-bromophenyl)vinyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}acetate

To a suspension of (4-bromobenzyl)triphenylphosphonium bromide (2.67 g)in dimethylsulphoxide (15 mL), potassium tert-butoxide (0.508 g) wasadded at 0° C. After stirring the reaction mixture for 30 minutes atroom temperature, a solution of the compound obtained from step e above(0.9 g) in tetrahydrofuran (5 mL) was added drop-wise at 0° C. Thereaction mixture was stirred for 2 hours and brought from 0° C. to roomtemperature, and quenched with ice cold water. The solvents wereevaporated, and ethyl acetate and water were added to resulting residue.The organic layer was separated, washed with water and brine solution,and dried over anhydrous sodium sulphate. The solvent was evaporatedunder reduced pressure, and the residue thus obtained was purified bycolumn chromatography using 10% ethyl acetate in hexane as eluant tofurnish the title compound (1.0 g).

Mass (m/z): 413.3 (M⁺+1)

Step g: Synthesis of ethyl{(3aR,5R,6R,6aR)-5-[(E)-2-(4′-chlorobiphenyl-4-yl)vinyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}acetate

A mixture of the compound obtained from step f above (1.0 g)(4-chlorophenyl)boronic acid (0.76 g),tetrakis(triphenylphosphine)palladium (0) (0.14 g), and potassiumcarbonate (1.0 g) in dry dimethylformamide (10 mL) was heated at 110° C.for 4 hours. Ethyl acetate and water were added to the reaction mixture.The organic layer was separated, washed with water and brine solution,and dried over anhydrous sodium sulphate. The solvent was evaporatedunder reduced pressure to obtain a residue which was purified by columnchromatography over silica gel using 12% ethyl acetate in hexane aseluant to afford the title compound (0.9 g).

Mass (m/z): 465.2 (M⁺+23)

Step h: Synthesis of ethyl{(3aR,5R,6R,6aR)-5-[2-(4′-chlorobiphenyl-4-yl)ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}acetate

To a solution of the compound obtained from step g above (0.8 g) inethyl acetate (15 mL), 10% palladium on charcoal (0.25 g) was added atroom temperature. The system was evacuated with hydrogen and thereaction mixture was stirred for 4 hours at room temperature under ahydrogen atmosphere. The reaction mixture was filtered through a celitepad, and concentrated to afford the title compound (0.75 g).

Mass (m/z): 415.4 (M⁺−28)

Step i: Synthesis of2-{(3aR,5R,6R,6aR)-5-[2-(4′-chlorobiphenyl-4-yl)ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethanol

To a solution of the compound obtained from step h above (0.75 g) intetrahydrofuran (15 mL), lithium aluminum hydride (0.096 g) was added at0° C. The resulting mixture was stirred for 3 hours at same temperature,and a saturated solution of ammonium chloride was then added. Thereaction mixture was then filtered through silica gel (100 to 200 mesh)and concentrated. Ethyl acetate and water were added to the resultingresidue. The organic layer was separated, washed with water and brine,dried over anhydrous sodium sulphate, filtered, and concentrated underreduced pressure to afford the title compound (0.65 g).

Mass (m/z): 425.2 (M⁺+23)

Step j: Synthesis of2-{(3aR,5R,6R,6aR)-5-[2-(4′-chlorobiphenyl-4-yl)ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethylmethanesulfonate

Triethylamine (0.43 ml) and methanesulfonyl chloride (0.21 mL) wereadded to a solution of the compound obtained from step i above (0.6 g)in dichloromethane (15 mL) at 0° C. The reaction mixture was stirred atroom temperature for 2 hours. Dichloromethane and water were added toreaction mixture. The organic layer was separated, washed with water,dried, and concentrated under reduced pressure to furnish the titlecompound (0.6 g).

Step k: Synthesis of2-(2-{(3aR,5R,6R,6aR)-5-[2-(4′-chlorobiphenyl-4-yl)ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1H-isoindole-1,3(2H)-dione

Potassium phthalimide (0.051 g) was added in one portion to a stirredsolution of the compound obtained from step j above (0.12 g) indimethylformamide (5 mL) at room temperature under a nitrogenatmosphere. The resulting solution was heated at 50° C. for about 14hours and then cooled to room temperature. Ethyl acetate and water wereadded to the reaction mixture. The organic layer was separated, washedwith water and brine, and dried over anhydrous sodium sulphate. Theorganic phase was evaporated to dryness under reduced pressure. Theresidue thus obtained was purified by column chromatography using 30%ethyl acetate in hexane as eluant to furnish the title compound (0.1 g).

Mass (m/z): 549.5 (M⁺+NH₄ ⁺)

Step l: Synthesis of2-(2-{(2R,3S,4R,5S)-2-[2-(4′-chlorobiphenyl-4-yl)ethyl]-4,5-dihydroxytetrahydrofuran-3-yl}ethyl)-1H-isoindole-1,3(2H)-dione

Trifluoroacetic acid (1 mL) and water (0.5 mL) were added to thecompound obtained from step k above (0.04 g). The reaction mixture wasstirred at room temperature for 2 hours. The solvents were evaporated atreduced pressure. The residue thus obtained was taken in ethyl acetateand water. The organic layer was separated, washed with water and brinesolution, and dried over anhydrous sodium sulphate. The solvent wasconcentrated under reduced pressure to yield the title compound (0.028g).

Step m: Synthesis of(2R,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-(formyloxy)pentanoicacid

To a solution of the compound obtained from step 1 above (0.028 g) in atert-butanol:water (2:3; 1.3 mL), sodium metaperiodate (0.051 g) wasadded at room temperature. The reaction mixture was stirred for 2 hoursat the same temperature, and potassium permanganate (0.001 g) was addedat 0° C. After stirring the reaction mixture for an additional 6 hoursat room temperature, the reaction mixture was evaporated on a rotaryevaporator, and the residue was taken into water and extracted withethyl acetate. The organic layer was washed with water and brinesolution, and dried over anhydrous sodium sulphate. The solvent wasevaporated under the reduced pressure to afford the title compound(0.025 g).

Step n: Synthesis of(2R,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoicacid

Potassium carbonate (0.007 g) was added to a solution of the compoundobtained from step m above (0.025 g) in methanol (1 mL) at 0° C. Thereaction mixture was stirred at room temperature for 3 hours. Thesolvents were evaporated and the residue was taken into water and ethylacetate. The organic layer was washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was evaporated underreduced pressure to obtain a residue which was purified by columnchromatography over silica gel using 10% methanol in dichloromethane aseluant to afford the title compound (0.014 g).

Mass (m/z): 478.2 (M⁺+1)

¹HNMR (CD₃OD): δ 7.83 (q, 2H, J=4 Hz), 7.77 (q, 2H, J=4 Hz), 7.56 (d,2H, J=8 Hz), 7.48 (d, 2H, J=8 Hz), 7.40 (d, 2H, J=8 Hz), 7.26 (d, 1H,J=8 Hz), 3.83-3.70 (m, 3H), 2.85-2.49 (m, 3H), 1.92-1.70 (m, 4H).

Example 5 Synthesis of(2R,3S)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoicacid (Compound No. 205) Step a: Synthesis of3-O-Acetyl-1,2:5,6-di-O-isopropylidene-α-D-erythrohexofuran-3-enose

Acetic anhydride (65.77 mL) was added to a solution of the compoundobtained from step a of Example 4 (45 g) in pyridine (500 mL) and thereaction mixture was heated at 60° C. for overnight. The reactionmixture was then concentrated to obtain a residue. Ethyl acetate andwater were added to the residue. The organic layer was separated andwashed with dilute hydrochloric acid, water, and brine. The solvent wasevaporated under reduced pressure and the residue thus obtained waspurified by silica gel column chromatography using 8% ethyl acetate inhexane as eluant to furnish the title compound (21 g).

Mass (m/z): 301.19 (M⁺+1)

Step b: Synthesis of3-O-acetyl-1,2:5,6-di-O-isopropylidene-α-D-gulofuranose

To a solution of the compound obtained from step a above (26 g) in ethylacetate (250 mL), 10% palladium on charcoal (6 g) was added and thereaction mixture was shaken under hydrogen atmosphere at 60 psi for 4hours on Paar apparatus. The reaction mixture was filtered through acelite bed. The solvents were evaporated to obtain a crude residue whichwas purified using column chromatography over silica gel using 15% ethylacetate in hexane as eluant to furnish the title compound (17 g).

Mass (m/z): 324.97 (M⁺+Na)

Step c: Synthesis of 1,2:5,6-di-O-isopropylidene-α-D-gulofuranose

Sodium methoxide (12.5 g) was added to a solution of the compoundobtained from step b above (64 g) in methanol (10 mL). The reactionmixture was stirred for 3 hours at 0° C. The reaction mixture was thenconcentrated. The residue thus obtained was purified by columnchromatography over silica gel using 30% ethyl acetate in hexane aseluant to afford the title compound (31 g).

Mass (m/z): 261.26 (M⁺+1)

Step d: Synthesis of1,2:5,6-di-O-isopropylidene-α-D-xylo-hexofuranos-3-ulose

Sodium hypochlorite (225 mL, 4% solution) was added drop-wise to asolution of the compound obtained from step c above (30 g), followed bythe addition of 2,2,6,6-tetramethylpiperidine N-oxyl (0.18 g), potassiumbromide (10.62 g), and sodium acetate (14.19 g) in ethyl acetate (300mL) and water (100 mL). After 20 minutes, triethylamine (3.3 mL) wasadded drop-wise to the above mixture at the same temperature. Thereaction mixture was extracted with ethyl acetate after 30 minutes. Theorganic layer was dried over anhydrous sodium sulphate. The solvent wasevaporated under reduced pressure to afford the title compound (10.4 g).

Step e: Synthesis of1,2:5,6-Di-O-isopropylidene-3-deoxy-3-(2-ethoxy-2-oxoethylidene)-α-D-xylo-hexofuranose

To the solution of the compound obtained from step d above (10.5 g) intetrahydrofuran, carboethoxymethylene triphenyl-phosphorane (27 g) wasadded. The reaction mixture was refluxed for 2 hours and concentrated toafford crude compound, which was purified by column chromatography oversilica gel using 8% ethyl acetate in hexane as eluant to yield the titlecompound (5.0 g).

Mass (m/z): 350.28 (M⁺+Na)

Step f: Synthesis of1,2:5,6-Di-O-isopropylidene-3-deoxy-3-(2-ethoxy-2-oxoethyl)-α-D-gulofuranose

10% Palladium on charcoal (3 g) was added to a solution of the compoundobtained from step e above (12 g) in methanol (50 mL) and the reactionmixture was stirred under hydrogen atmosphere at room temperature for 4hours. The reaction mixture was filtered through a celite pad and theresidue was washed using ethyl acetate. The filtrate was concentrated tofurnish the title compound (12 g).

Mass (m/z): 330.9 (M⁺+1).

Step g: Synthesis of1,2:5,6-Di-O-isopropylidene-3-deoxy-3-(2-hydroxyethyl)-α-D-gulofuranose

To a suspension of lithium aluminum hydride (2.37 g) in tetrahydrofuran(120 mL), a solution of the compound obtained from step f above (12 g)in tetrahydrofuran (100 mL) was added at −50° C. The reaction mixturewas allowed to attain the temperature 0° C. and the mixture was stirredfor 30 minutes at 0° C. The reaction mixture was quenched using anaqueous solution of ammonium chloride (25 mL). The reaction mixture wasslowly allowed to attain room temperature and was further stirred for 12hours at same temperature. The reaction mixture was filtered through acelite pad, and the residue was washed with ethyl acetate. The organiclayer was dried over anhydrous sodium sulphate. The solvent wasevaporated under reduced pressure to afford the title compound (8.5 g).

Step h: Synthesis of1,2:5,6-Di-O-isopropylidene-3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-α-D-gulofuranose

A mixture of the compound obtained from step g above (8.5 g), triphenylphosphine (21.83 g), and phthalimide (6.73 g) were taken in a roundbottom flask and dried in high vacuum for 10 minutes. Then the vacuumwas released under a nitrogen atmosphere and tetrahydrofuran (100 mL)was added to the reaction mixture. The reaction mixture was cooled to 0°C. and diisopropyl azodicarboxylate (12.625 g) was added slowly. Thereaction mixture was stirred for 30 minutes at the same temperature andthen quenched with water and extracted with ethyl acetate. The organiclayer was washed with water and brine solution, dried over anhydroussodium sulphate, and concentrated. The residue thus obtained waspurified by column chromatography over silica gel using 40% ethylacetate in hexane as eluant to afford the title compound (8.5 g).

Step i: Synthesis of3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-1,2-O-(isopropylidene)-α-D-gulofuranose

30% Perchloric acid (8.15 mL) was added to a solution of the compoundobtained from step h above (0.8 g) in tetrahydrofuran (200 mL). Thereaction mixture was stirred for 2 hours at 0° C. to 5° C. and thenquenched with a saturated solution of sodium hydrogen carbonate. Ethylacetate and water were added to the resulting mixture. The organic layerwas separated, washed with brine, dried over anhydrous sodium sulphate,and concentrated. The residue thus obtained was purified by columnchromatography over silica gel using 60% ethyl acetate in hexane toafford the title compound (5.5 g).

Mass (m/z): 377.24 (M⁺+1)

Step j: Synthesis of(5R)-3-deoxy-3-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-4,5-O-(1-methylethylidene)-L-arabino-pentodialdo-5,2-furanose

To a solution of the compound obtained from step i above (5.5 g) inacetone (100 mL), an aqueous solution of sodium periodate (9.33 g in 100mL) was added at 0° C. The reaction mixture was stirred for 2 hours,then filtered and concentrated. The residue thus obtained was taken indistilled water and extracted with ethyl acetate. The organic layer wasdried over sodium sulphate and concentrated to afford the title compound(5.2 g).

Step k: Synthesis of2-(2-{(3aR,5S,6R,6aR)-5-[(E)-2-(4-bromophenyl)ethenyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1H-isoindole-1,3(2H)-dione

A solution of (4-bromobenzyl)triphenylphosphonium bromide (13.3 g) indimethyl sulphoxide (10 mL) was added drop-wise to a suspension ofsodium hydride (1 g of 50% suspension) in dimethyl sulphoxide (20 mL) at0° C. After 20 minutes, a solution of the compound obtained from step jabove (6 g) in dimethylsulphoxide (100 mL) was added drop-wise and thereaction mixture was stirred for 1 hour at the same temperature. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water and brine solution anddried over anhydrous sodium sulphate. The solvent was evaporated underreduced pressure to obtain a residue which was purified by columnchromatography over silica gel using 40% ethyl acetate in hexane tofurnish the title compound (5.5 g).

Mass (m/z): 499.10 (M⁺+1)

Step l: Synthesis of2-(2-{(3aR,5S,6R,6aR)-5-[(E)-2-(3′-fluoro-4′-methylbiphenyl-4-yl)ethenyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1H-isoindole-1,3(2H)-dione

A mixture of the compound obtained from step k above (0.5 g),3-fluoro-4-methylphenylboronic acid (0.314 g),tetrakistriphenylphosphinepalladium (0) (0.057 g), and potassiumcarbonate (0.414 g) was dried under high vacuum for 10 minutes. Thevacuum was released under nitrogen atmosphere and dry dimethylformamide(5 mL) was added at room temperature. The reaction mixture was heated at120° C. for 2 hours, and then quenched with water and extracted withethyl acetate. The organic layer was washed with water and brinesolution, and dried over anhydrous sodium sulphate. The solvent wasevaporated under reduced pressure to obtain a residue which was purifiedby column chromatography over silica gel using 30% ethyl acetate inhexane as eluant to afford the title compound (0.37 g).

Mass (m/z): 527.23 (M⁺+1)

Step m: Synthesis of2-(2-{(3aR,5S,6R,6aR)-5-[2-(3′-fluoro-4′-methylbiphenyl-4-yl)ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1H-isoindole-1,3(2H)-dione

10% Palladium on charcoal (100 g) was added to a solution of thecompound obtained from step 1 above (0.37 g) in ethyl acetate (10 mL) atroom temperature and the reaction mixture was hydrogenated at 35 psi for1 hour in a Paar apparatus. The reaction mixture was filtered through acelite pad and the residue was washed with methanol. The filtrate wasconcentrated to afford the title compound (0.28 g).

Step n: Synthesis of2-(2-{(2S,3S,4R,5S)-2-[2-(3′-fluoro-4′-methylbiphenyl-4-yl)ethyl]-4,5-dihydroxytetrahydrofuran-3-yl}ethyl)-1H-isoindole-1,3(2H)-dione

To a solution of the compound obtained from step m above (0.28 g) inacetonitrile (20 mL) and water (2 mL), 30% perchloric acid (0.4 mL) wasadded at room temperature. The reaction mixture was heated to 55° C. for30 minutes. The reaction mixture was then quenched using a sodiumbicarbonate solution. The solvents were evaporated at reduced pressure.The residue thus obtained was taken in ethyl acetate and water. Theorganic layer was separated, washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was concentrated underreduced pressure to yield the title compound (0.418 g) as crude masswhich was used further without any purification and characterization.

Step o: Synthesis of(2R,3S)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-(formyloxy)pentanoicacid

A solution of sodium metaperiodate (0.489 g in 5 mL of water) was addedto a solution of the compound, obtained from step n above (0.4 g), in atert-butanol:tetrahydrofuran (5 mL:5 mL) at 0° C. The reaction mixturewas stirred for 2 hours at the same temperature and potassiumpermanganate (0.033 g) was added at 0° C. After stirring the reactionmixture for an additional 6 hours at room temperature, the reactionmixture was evaporated on a rotary evaporator, and the residue was takeninto water and extracted with ethyl acetate. The organic layer waswashed with water and brine solution and dried over anhydrous sodiumsulphate. The solvent was evaporated under reduced pressure to affordthe title compound (0.31 g) as crude mass which was used further withoutany purification and characterization.

Step p: Synthesis of(2R,3S)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoicacid

To a solution of the compound obtained from step o above (0.31 g) inmethanol (5 mL), potassium carbonate (0.094 g) was added at 0° C. Thereaction mixture was stirred at room temperature for 3 hours. Thereaction mixture was diluted with ethyl acetate (50 mL), acidified withsodium hydrogen sulphate, and washed with water (20 mL). The organiclayer was dried over anhydrous sodium sulphate and concentrated underreduced pressure to obtain a residue which was purified by preparativethin layer chromatography using 10% methanol in dichloromethane aseluant to afford the title compound (0.020 g).

Mass (m/z): 476.07 (M⁺+1)

¹HNMR (CD₃OD): δ 7.72-7.64 (m, 4H), 7.36-7.34 (m, 2H), 7.18-7.10 (m,5H), 3.68-3.61 (m, 3H), 2.75-2.71 (m, 1H), 2.55-2.49 (s, 1H), 2.32-2.30(m, 1H), 2.16 (s, 3H), 1.99-1.94 (m, 2H), 1.70-1.62 (m, 2H).

Example 6 Synthesis of(2S,3S)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 208) Step a: Synthesis of5-O-[tert-butyl(diphenyl)silyl]-3-deoxy-1,2-O-isopropylidene-3-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-α-L-ribofuranose

A mixture of the compound obtained from step f of Example 1 (20 g),triphenyl phosphine (17.6 g), and 1,2,3-benzotriazin-4(3H)-one (7.2 g)was dried in high vacuum in a round bottom flask for 10 minutes. Thevacuum was released under a nitrogen atmosphere and tetrahydrofuran (200mL) was added to the above reaction mixture. The reaction mixture wascooled to 0° C. and diisopropyl azodicarboxylate (9.8 mL) was addedslowly. The reaction mixture was stirred for 30 minutes at the sametemperature, and then quenched with water and extracted with ethylacetate. The organic layer was washed with water and brine solution,dried over anhydrous sodium sulphate, and concentrated to obtain aresidue which was purified by column chromatography over silica gelusing 30% ethyl acetate in hexane as eluant to afford the title compound(22 g).

Mass (m/z): 586.24 (M⁺+1).

Step b: Synthesis of3-deoxy-1,2-O-isopropylidene-3-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-α-L-ribofuranose

To a solution of the compound obtained from step a above (22 g) in drytetrahydrofuran (200 mL) at 0° C., 1 M solution of tetra-butylammoniumfluoride (75 mL) was added. The resulting mixture was stirred at 0° C.for 1 hour and then at room temperature for 4 hours. The reactionmixture was cooled to 0° C., quenched with saturated ammonium chlorideand extracted with ethyl acetate. The organic layer was washed withwater and brine, dried over anhydrous sodium sulphate, and concentrated.The residue thus obtained was purified by column chromatography oversilica gel using 50% ethyl acetate in hexane as eluant to furnish thetitle compound (6.5 g).

Mass (m/z): 348.25 (M⁺+1)

Step c: Synthesis of(5S)-3-deoxy-4,5-O-isopropylidene-3-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-D-ribo-pentodialdo-5,2-furanose

To a solution of the compound obtained from step b above (6.5 g) in drydichloromethane (100 mL) cooled to 0° C., Dess-Martin periodinanereagent (11.1 g) was added. The reaction mixture was allowed to stir for2 hours. The reaction mixture was quenched with sodium thiosulphate andsodium hydrogen carbonate. Dichloromethane was added to the reactionmixture. The organic layer was separated, washed with water and brinesolution, dried over sodium sulphate, and evaporated to afford the titlecompound. (6.5 g)

Step d: Synthesis of3-(2-{(3aS,5S,6S,6aS)-5-[(E)-2-(4-bromophenyl)vinyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

To a suspension of sodium hydride (0.979 g, 60% in oil) in dimethylsulphoxide (60 mL) cooled to 0° C., (4-bromobenzyl)triphenylphosphoniumbromide (14.5 g) was added. The compound obtained from step c above (6.5g) in tetrahydrofuran (60 mL) was added drop-wise after 20 minutes, andthe reaction mixture was stirred for 1 hour at the same temperature. Thereaction mixture was quenched with water and extracted with ethylacetate. The organic layer was washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was evaporated underreduced pressure and the residue thus obtained was purified by columnchromatography using 40% ethyl acetate in hexane as eluant to furnishthe title compound (4 g).

Mass (m/z): 498.19 (M⁺+1)

Step e: Synthesis of3-(2-{(3aS,5S,6S,6aS)-5-[(E)-2-(4′-methoxybiphenyl-4-yl)vinyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

A mixture of the compound obtained from step d above (1 g),4-methoxyphenyl boronic acid (0.61 g), tetrakistriphenylphosphinepalladium (0) (0.232 g), and potassium carbonate (0.832 g) was driedunder high vacuum for 10 minutes and dry dimethylformamide (20 mL) wasadded at room temperature. The reaction mixture was heated at 120° C.for 2 hours, and then quenched with water and extracted with ethylacetate. The organic layer was washed with water and brine solution, anddried over anhydrous sodium sulphate. The solvent was evaporated underreduced pressure to obtain a residue which was purified by columnchromatography over silica gel using 50% ethyl acetate in hexane aseluant to afford the title compound (0.62 g).

Mass (m/z): 526.41 (M⁺+1)

Step f: Synthesis of3-(2-{(3aS,5S,6S,6aS)-5-[2-(4′-methoxybiphenyl-4-yl)ethyl]-2,2-dimethyltetrahydrofuro[2,3-d][1,3]dioxol-6-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

To a solution of the compound obtained from step e above (0.62 g) in asolvent mixture of ethyl acetate (20 mL), 10% palladium on charcoal (0.3g) was added at room temperature, and the reaction mixture washydrogenated at 35 psi for 4 hours in a Paar apparatus. The reactionmixture was filtered through a celite pad and the residue was washedwith methanol. The filtrate was concentrated to afford the titlecompound (0.6 g).

Step g: Synthesis of3-(2-{(2S,3R,4S,5R)-4,5-dihydroxy-2-[2-(4′-methoxybiphenyl-4-yl)ethyl]tetrahydrofuran-3-yl}ethyl)-1,2,3-benzotriazin-4(3H)-one

Perchloric acid (0.2 mL) was added to a solution of the compoundobtained from step f above (0.6 g) in acetonitrile (50 mL) and water (10mL) at room temperature. The reaction mixture was heated to 55° C. for30 minutes. The reaction mixture was then quenched using a sodiumhydrogen carbonate solution. The solvents were evaporated at reducedpressure. The residue thus obtained was taken in ethyl acetate andwater. The organic layer was separated, washed with water and brinesolution, and dried over anhydrous sodium sulphate. The solvent wasconcentrated under reduced pressure to yield the title compound (0.6 g).

Step h: Synthesis of(2S,3S)-3-(formyloxy)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoicacid

To a solution of the compound obtained from step g above (0.6 g) in atert-butanol:tetrahydrofuran (7 mL:7 mL), a solution of sodiummetaperiodate (0.973 g in 7 mL of water) was added at 0° C. The reactionmixture was stirred for 2 hours at the same temperature and potassiumpermanganate (0.036 g) was added at 0° C. After stirring the reactionmixture for an additional 6 hours at room temperature, the reactionmixture was evaporated and the residue was taken into water andextracted with ethyl acetate. The organic layer was washed with waterand brine solution and dried over anhydrous sodium sulphate. The solventwas evaporated under reduced pressure to afford the title compound (0.5g).

Step i: Synthesis of(2S,3S)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid

Potassium carbonate (0.151 g) was added to a solution of the compoundobtained from step h above (0.5 g) in methanol (5 mL) andtetrahydrofuran (5 mL) at 0° C. The reaction mixture was stirred at roomtemperature for 3 hours. The solvents were evaporated and the residuewas taken into water and ethyl acetate. The organic layer was washedwith water and brine solution, and dried over anhydrous sodium sulphate.The solvent was evaporated under reduced pressure to obtain a residuewhich was purified by preparative thin layer chromatography using 10%methanol in dichloromethane as eluent to afford the title compound(0.008 g).

Mass (m/z): 474.31 (M⁺+1);

¹HNMR (CD₃OD): δ 8.32-7.87 (m, 5H), 7.50-7.42 (m, 4H), 7.24-7.20 (m,2H), 6.97-6.94 (m, 1H), 4.60-4.50 (m, 2H), 3.81 (s, 3H), 3.59 (br t,1H), 3.0-1.8 (m, 7H).

Example 7 Synthesis of(2S,3R)-3-hydroxy-5-[4-(5-methylpyridin-2-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 209) Step a: Synthesis of4-(5-methylpyridin-2-yl)benzaldehyde

A mixture of 2-bromo-5-methylpyridine (2 g), (4-formylphenyl)boronicacid (3.5 g), tetrakis(triphenylphosphine)palladium(0) (0.672 g), andpotassium carbonate (4.8 g) was dried under high vacuum for 10 minutesand dry dimethylformamide (15 mL) was added at room temperature. Thereaction mixture was heated at 110° C. for 6 hours, and then quenchedwith water and extracted with ethyl acetate. The organic layer waswashed with water and brine solution, and dried over anhydrous sodiumsulphate. The solvent was evaporated under reduced pressure to obtain aresidue which was purified by column chromatography over silica gelusing 20% ethyl acetate in hexane as eluant to afford the title compound(2.8 g).

Mass (m/z): 198.20

Step b: Synthesis of ethyl(2E)-3-[4-(5-methylpyridin-2-yl)phenyl]prop-2-enoate

To a suspension of sodium hydride (0.682 g, 60% in oil.) intetrahydrofuran (20 mL), triethyl phosphonoacetate (3.82 g) was chargedat 0° C. After 15 minutes, a solution of the compound obtained from stepa above (2.8 g) in tetrahydrofuran (5 mL) was added drop-wise, and thereaction mixture was stirred for 30 minutes at room temperature. Asaturated solution of ammonium chloride in water was added to thereaction mixture. The solvent was evaporated and the resulting mixturewas extracted with ethyl acetate. The combined extracts were dried overanhydrous sodium sulphate and evaporated under reduced pressure to yielda residue which was purified by column chromatography over silica gelusing 15% ethyl acetate in hexane as eluant to afford the title compound(1.8 g).

Step c: Synthesis of ethyl 3-[4-(5-methylpyridin-2-yl)phenyl]propanoate

10% Palladium on charcoal (0.8 g) was added to a solution of thecompound obtained from step b above (1.8 g) in tetrahydrofuran (15 mL)at room temperature, and hydrogen was supplied at 50 psi in a Paarapparatus for 4 hours. The reaction mixture was filtered through acelite pad and concentrated to afford the title compound (1.8 g).

Step d: Synthesis of 3-[4-(5-methylpyridin-2-yl)phenyl]propan-1-ol

To a suspension of lithium aluminum hydride (0.424 g) in tetrahydrofuran(20 mL), a solution of the compound obtained from step c above (2 g) intetrahydrofuran (10 mL) was added at −20° C. The reaction mixture wasstirred for 2 hours at 30° C. and a saturated solution of sodiumsulphate was added at the same temperature. The reaction mixture wasthen filtered through a celite pad and the residue was washed with ethylacetate. The organic layer was dried over anhydrous sodium sulphate,filtered, and concentrated under reduced pressure. The residue thusobtained was purified by column chromatography over silica gel using 50%ethyl acetate in hexane as eluant to afford the title compound (1.2 g).

Step e: Synthesis of 3-[4-(5-methylpyridin-2-yl)phenyl]propanal

To a stirred solution of the compound obtained from step d above (1.4 g)in dichloromethane (20 mL), 2,2,6,6-tetramethylpiperidine N-oxyl (9.6mg) and potassium bromide (73.4 mg) were added at 0° C. under nitrogenatmosphere. Sodium hypochlorite (13.7 mL, 4% solution) was added at pH8-9 (maintained by adding aqueous sodium bicarbonate solution). Thereaction was stirred for 20 minutes at 0° C. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate solution, water, and brine. The organic layer was dried overanhydrous sodium sulphate, filtered, and concentrated under reducedpressure to afford the title compound (0.9 g).

Step f: Synthesis of3-{(3S,4R)-3-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]carbonyl}-4-hydroxy-6-[4-(5-methylpyridin-2-yl)phenyl]hexyl}-1,2,3-benzotriazin-4(3H)-one

In a flame-dried flask,3-{4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-4-oxobutyl}-1,2,3-benzotriazin-4(3H)-one(1.18 g) was taken up in dichloromethane (10 mL) and cooled to 0° C.Titanium tetrachloride (3.4 mL) in dichloromethane (6 mL) was addeddrop-wise and the reaction mixture was stirred for 10 to 15 minutes.(−)-Sparteine (1.7 g) was added slowly to the reaction mixture andstirred at 0° C. for 45 minutes. A solution of the compound obtainedfrom step e above (0.65 g) in dichloromethane (10 mL) was added slowlyand stirring was continued at 0° C. After 3 hours, the reaction wasquenched with the drop-wise addition of a saturated ammonium chloridesolution, and dichloromethane was added. The organic layer was separatedand the aqueous layer was extracted with dichloromethane. The organiclayer was washed with brine, dried over anhydrous sodium sulphate, andconcentrated under reduced pressure. The crude product thus obtained waspurified by silica gel flash column chromatography using 30% ethylacetate in hexane as eluant to afford the aldol adduct (0.56 g).

Step g: Synthesis of(2S,3R)-3-hydroxy-5-[4-(5-methylpyridin-2-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid

To a stirred solution of the compound obtained from step f above (0.2 g)in tetrahydrofuran:water (3:1, 10 mL), aqueous hydrogen peroxidesolution (30%, 0.16 mL) was added at 0° C. followed by the addition oflithium hydroxide monohydrate (0.02 g) in water (5 mL). The reactionmixture was stirred at 0° C. for 30 minutes. The reaction mixture wasconcentrated, and the residue was extracted with ethyl acetate. Theaqueous layer was acidified with sodium hydrogen sulphate and extractedwith ethyl acetate. The combined layers were washed with water andbrine, and dried over anhydrous sodium sulphate. The solvents wereevaporated under reduced pressure and the crude residue was purified bysilica gel flash column chromatography using 3% methanol indichloromethane as eluant to afford the title compound (0.035 g).

Mass (m/z): 459.21 (M⁺+1);

¹HNMR (CD₃OD): δ 8.40 (s, 1H), 8.30 (d, 1H, J=7.88 Hz), 8.15 (d, 1H, J=8Hz), 8.05-7.70 (m, 6H), 7.27 (d, 2H, J=7.6 Hz), 4.40-4.0 (m, 2H),3.80-3.60 (m, 1H), 2.80-2.40 (m, 5H), 2.38 (s, 3H), 1.80-1.60 (m, 2H).

Example 7A Synthesis of(2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 86) Step a: Synthesis of methyl(2E)-3-(4-bromophenyl)prop-2-enoate

To a stirred solution of 4-bromocinnamic acid (16 g) in methanol (150mL), thionyl chloride (30 mL) was added at 0° C. The reaction mixturewas warmed to room temperature and refluxed for 3 hours. After coolingto room temperature, the solvents were evaporated to dryness. The crudecompound obtained was used as such for the next step.

Step b: Synthesis of methyl(2E)-3-[4-(6-methoxypyridin-3-yl)phenyl]prop-2-enoate

The compound obtained from step a above (7.5 g),pyridine-2-methoxy-5-boronic acid (9.48 g),tetrakis(triphenylphosphine)palladium(0) (1.79 g), and potassiumcarbonate (12.83 g) were taken in dimethylformamide (60 mL) undernitrogen atmosphere. The reaction mixture was refluxed under nitrogenatmosphere for 6 hours. After cooling to room temperature, water wasadded and the reaction mixture was extracted with ethyl acetate. Thecombined organic layers were washed with water and brine, dried overanhydrous sodium sulfate, and the solvents were evaporated under reducedpressure. The crude product was purified by silica gel flash columnchromatography using 20% to 30% ethyl acetate in hexane to get the titlecompound (8.09 g).

Step c: Synthesis of methyl3-[4-(6-methoxypyridin-3-yl)phenyl]propanoate

To a solution of compound obtained from step b above (8.1 g) in amixture of ethyl acetate/methanol/tetrahydrofuran (˜300 mL), 10%Palladium on charcoal (1.6 g) was added and stirred under hydrogenatmosphere at 30 psi in a Paar apparatus for 2.5 hours. The reactionmixture was filtered through a celite pad, washed with ethyl acetate,and the filtrate was concentrated under reduced pressure to obtain thetitle compound as a white solid which was used as such for the nextstep.

Step d: Synthesis of 3-[4-(6-methoxypyridin-3-yl)phenyl]propanoic acid

To a stirred solution of lithium aluminum hydride (2.28 g) intetrahydrofuran (120 mL), the compound obtained from step c above (8 g)in tetrahydrofuran (50 mL) was added at 0° C. The reaction mixture wasstirred at 0° C. for 3 hours. The reaction mixture was quenchedcarefully with saturated ammonium chloride solution, filtered throughcelite, and washed with ethyl acetate. The organic layers wereseparated, washed with brine, and dried over anhydrous sodium sulfate,and solvents were evaporated under reduced pressure. The crude productwas purified by silica gel flash column chromatography using 20% to 30%ethyl acetate in hexane to get the title compound as a white crystallinesolid (5.1 g).

Step e: Synthesis of 3-[4-(6-methoxypyridin-3-yl)phenyl]propanal

To a stirred solution of the compound obtained from step d above (9.0 g)in dichloromethane (90 ml), 2,2,6,6-tetramethylpiperidine N-oxyl (58.77mg) and potassium bromide (447.57 mg) were added at 0° C. under nitrogenatmosphere. A 4% aqueous sodium hypochlorite (3.497 g) was added at pH8-9 (maintained by adding saturated aqueous sodium bicarbonatesolution). The reaction was stirred for 20 minutes at 0° C. Then, theorganic layer was separated and the aqueous layer was extracted withdichloromethane. The combined organic layers were washed with saturatedaqueous sodium bicarbonate solution, water, and brine. Finally, theorganic layers were dried over anhydrous sodium sulfate and concentratedunder reduced pressure to afford the title compound (8.1 g) which wasused as such in the next step.

Step f: Synthesis of3-{(3S,4S)-3-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]carbonyl}-4-hydroxy-6-[4-(5-methoxypyridin-2-yl)phenyl]hexyl}-1,2,3-benzotriazin-4(3H)-one

In a flame-dried flask,3-{4-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-4-oxobutyl}-1,2,3-benzotriazin-4(3H)-one(2.0 g) was taken up in dichloromethane (10 mL) and cooled to 0° C.Titanium tetrachloride (0.619 mL) in dichloromethane (6 mL) was addeddrop-wise and the reaction mixture was stirred for 10-15 minutes.(−)-Sparteine (2.7 mL) was added slowly to the reaction mixture andstirred at 0° C. for 45 minutes. A solution of the compound obtainedfrom step e above (1.34 g) in dichloromethane (10 mL) was added slowlyand stirring was continued at 0° C. After 3 hours, the reaction wasquenched with the drop-wise addition of saturated ammonium chloridesolution, and dichloromethane was added. The organic layer was separatedand the aqueous layer was extracted with dichloromethane. The organiclayer was washed with brine, dried over anhydrous sodium sulphate, andconcentrated under reduced pressure. The crude product thus obtained waspurified by silica gel flash column chromatography using 30% ethylacetate in hexane as eluant to afford the aldol adduct (1.21 g).

Step g: Synthesis of(2S,3R)-3-hydroxy-5-[4-(5-methoxypyridin-2-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid

To a stirred solution of the compound obtained from step f above (1.21g) in tetrahydrofuran:water (3:1, 15 mL), aqueous hydrogen peroxidesolution (30%, 1.02 mL) was added at 0° C., followed by addition oflithium hydroxide monohydrate (114.5 mg) in water (5 mL). The reactionmixture was stirred at 0° C. until the completion of the hydrolysis. Thereaction mixture was concentrated and the residue was extracted withethyl acetate. The aqueous layer was acidified with sodium hydrogensulphate and extracted with ethyl acetate. The combined layers werewashed with water and brine, and dried over anhydrous sodium sulphate.The solvents were evaporated under reduced pressure and the cruderesidue was purified by silica gel flash column chromatography using 3%methanol in dichloromethane as eluant to afford the title compound (0.61g).

Mass (m/z): 474.87 (M⁺+1);

¹H NMR (400 MHz, MeOD): δ 8.32-8.30 (2H, m), 8.16-8.14 (1H, m),8.04-8.03 (1H, m), 7.92-7.88 (2H, m), 7.46 (2H, d, J=8 Hz), 7.24 (2H, m,J=8 Hz), 6.86 (1H, d, J=8 Hz), 4.57-4.53 (2H, m), 3.93 (3H, s),3.78-3.83 (1H, m), 2.83-2.80 (1H, m), 2.63-2.60 (1H, m), 2.52-2.49 (1H,m), 2.32-2.28 (2H, m), 1.80-1.76 (2H, m).

Example 7B Synthesis of(2S,3R)-5-(2′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoicacid (Compound No. 216) Step a: Synthesis of methyl(2E)-3-(4-bromophenyl)prop-2-enoate

To a stirred solution of 4-bromocinnamic acid (16 g) in methanol (150mL), thionyl chloride (30 mL) was added at 0° C. The reaction mixturewas warmed to room temperature and refluxed for 3 hours. After coolingto room temperature, the solvents were evaporated to dryness. The crudecompound obtained was used as such for the next step.

Step b: Synthesis of methyl(2E)-3-(3′,5′-difluorobiphenyl-4-yl)prop-2-enoate

The compound obtained from step a above (0.75 g), 2,4-difluorophenylboronic acid (0.737 g), tetrakis(triphenylphosphine)palladium(0) (0.07g), and potassium carbonate (1.28 g) were taken in dimethylformamide (6mL) under nitrogen atmosphere. The reaction mixture was refluxed undernitrogen atmosphere for 6 hours. After cooling to room temperature,water was added and the reaction mixture was extracted with ethylacetate. The combined organic layers were washed with water and brine,dried over anhydrous sodium sulfate, and the solvents were evaporatedunder reduced pressure. The crude product was purified by silica gelflash column chromatography using 20% to 30% ethyl acetate in hexane toget the title compound (0.810 g).

Step c: Synthesis of methyl 3-(3′,5′-difluorobiphenyl-4-yl)propanoate

To a solution of the compound obtained from step b above (0.79 g) in amixture of ethyl acetate (˜10 mL), 10% Palladium on charcoal (0.2 g) wasadded and stirred under hydrogen atmosphere at 30 psi for 2.5 hours. Thereaction mixture was filtered through a celite pad washed with ethylacetate and the filtrate was concentrated under reduced pressure toobtain the title compound (0.77 g) as white solid which was used as suchfor the next step.

Step d: Synthesis of 3-(3′,5′-difluorobiphenyl-4-yl)propanoic acid

To a stirred solution of lithium aluminum hydride (0.2 g) intetrahydrofuran (15 mL), the compound obtained from step c above (0.77g) in tetrahydrofuran (50 mL) was added at 0° C. The reaction mixturewas stirred at 0° C. for 3 hours. The reaction mixture was quenchedcarefully with saturated ammonium chloride solution, filtered through acelite pad, and washed with ethyl acetate. The organic layers wereseparated, washed with brine, and dried over anhydrous sodium sulfate,and solvents were evaporated under reduced pressure. The crude productwas purified by silica gel flash column chromatography using 20% to 30%ethyl acetate in hexane to get the title compound as a white crystallinesolid (0.70 g).

Step e: Synthesis of 3-(3′,5′-difluorobiphenyl-4-yl)propanal

To a stirred solution of the compound obtained from step d above (0.7 g)in dichloromethane (10 mL), 2,2,6,6-tetramethylpiperidine N-oxyl (4.36mg) and potassium bromide (33.32 mg) were added at 0° C. under nitrogenatmosphere. Sodium hypochlorite (6.5 mL, 4% solution) was added at pH8-9 (maintained by adding aqueous sodium bicarbonate solution). Thereaction was stirred for 20 minutes at 0° C. The organic layer wasseparated and the aqueous layer was extracted with dichloromethane. Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate solution, water, and brine. The organic layer was dried overanhydrous sodium sulphate, filtered, and concentrated under reducedpressure to afford the title compound (0.57 g).

Step f: Synthesis of3-[(2R,3S)-2-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]carbonyl}-5-(3′,5′-difluorobiphenyl-4-yl)-3-hydroxypentyl]-1,2,3-benzotriazin-4(3H)-one

In a flame-dried flask,3-{3-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one(0.25 g) was taken up in dichloromethane (10 mL) and cooled to 0° C.Titanium tetrachloride (0.76 mL, 1 M solution) was added drop-wise andthe reaction mixture was stirred for 10 to 15 minutes. (−)-Sparteine(0.36 mL) was added slowly to the reaction mixture and stirred at 0° C.for 20 minutes. A solution of the compound obtained from step e above(0.187 g) in dichloromethane (10 mL) was added slowly and stirring wascontinued at 0° C. After 3 hours, the reaction was quenched with thedrop-wise addition of saturated ammonium chloride solution, anddichloromethane was added. The organic layer was separated and theaqueous layer was extracted with dichloromethane. The organic layer waswashed with brine, dried over anhydrous sodium sulphate, andconcentrated under reduced pressure. The crude product thus obtained waspurified by silica gel flash column chromatography using 30% ethylacetate in hexane as eluant to afford the title compound (0.24 g).

Step g: Synthesis of(2S,3R)-5-(3′,5′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoicacid

To a stirred solution of the compound obtained from step f above (0.2 g)in tetrahydrofuran:water (3:1, 10 mL) aqueous hydrogen peroxide solution(30%, 0.16 mL) was added at 0° C., followed by the addition of lithiumhydroxide monohydrate (19.53 mg) in water (2 mL). The reaction mixturewas stirred at 0° C. until the completion of the hydrolysis. Thereaction mixture was concentrated and the residue was extracted withethyl acetate. The aqueous layer was acidified with sodium hydrogensulphate and extracted with ethyl acetate. The combined layers werewashed with water and brine and dried over anhydrous sodium sulphate.The solvents were evaporated under reduced pressure, and the cruderesidue was purified by silica gel flash column chromatography using 10%methanol in dichloromethane as eluant to afford the title compound(0.090 g).

Mass (m/z): 466.06 (M⁺+1);

¹HNMR (CD₃OD): δ 8.17-8.8.15 (m, 1H), 8.05-8.01 (m, 1H), 7.90-7.88 (m,1H), 7.86-7.84 (m, 1H), 7.46-7.42 (m, 2H), 7.40-7.29 (m, 2H), 7.03-6.98(m, 2H), 4.82-4.84 (m, 2H), 3.94 (s, 1H), 3.22-3.21 (m, 1H), 2.91-2.89(m, 1H), 2.78-2.75 (m, 1H), 1.94-1.90 (m, 2H).

Example 7C Synthesis of(2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoicacid (Compound No. 217) Step a: Synthesis of methyl(2E)-3-(4-bromophenyl)prop-2-enoate

To a stirred solution of 4-bromocinnamic acid (16 g) in methanol (150mL), thionyl chloride (30 mL) was added at 0° C. The reaction mixturewas warmed to room temperature and refluxed for 3 hours. After coolingto room temperature, the solvents were evaporated to dryness. The crudecompound obtained was used as such for the next step.

Step b: Synthesis of methyl (2E)-3-(4′-fluorobiphenyl-4-yl)prop-2-enoate

The compound obtained from step a above (0.75 g), 4-fluorophenyl boronicacid (0.65 g), tetrakis(triphenylphosphine)palladium(0) (0.07 g), andpotassium carbonate (1.28 g) were taken in dimethylformamide (6 mL)under nitrogen atmosphere. The reaction mixture was refluxed undernitrogen atmosphere for 6 hours. After cooling to room temperature,water was added and the reaction mixture was extracted with ethylacetate. The combined organic layers were washed with water and brineand dried over anhydrous sodium sulfate, and the solvents wereevaporated under reduced pressure. The crude product was purified bysilica gel flash column chromatography using 20% to 30% ethyl acetate inhexane to get the title compound (0.720 g).

Step c: Synthesis of methyl 3-(4′-fluorobiphenyl-4-yl) propanoate

To a solution of the compound obtained from step b above (0.7 g) in amixture of ethyl acetate (˜20 mL), 10% palladium on charcoal (0.2 g) wasadded and stirred under hydrogen atmosphere at 30 psi in a Paarapparatus for 2.5 hours. The reaction mixture was filtered through acelite pad, washed with ethyl acetate, and the filtrate was concentratedunder reduced pressure to obtain the title compound (0.7 g) as a whitesolid which was used as such for the next step.

Step d: Synthesis of 3-(4′-fluorobiphenyl-4-yl)propanoic acid

To a stirred solution of lithium aluminium hydride (0.2 g) intetrahydrofuran (15 mL), the compound obtained from step c above (0.7 g)in tetrahydrofuran (50 mL) was added at 0° C. The reaction mixture wasstirred at 0° C. for 3 hours. The reaction mixture was quenchedcarefully with saturated ammonium chloride solution, filtered through acelite pad, and washed with ethyl acetate. The organic layers wereseparated, washed with brine, and dried over anhydrous sodium sulfate,and solvents were evaporated under reduced pressure. The crude productwas purified by silica gel flash column chromatography using 20% to 30%ethyl acetate in hexane to get the title compound as a white crystallinesolid (0.70 g).

Step e: Synthesis of 3-(4′-fluorobiphenyl-4-yl)propanal

To a stirred solution of the compound obtained from step d above (0.7 g)in dichloromethane (10 mL), 2,2,6,6-tetramethylpiperidine N-oxyl (4.74mg) and potassium bromide (36.05 mg) were added at 0° C. under nitrogenatmosphere. Sodium hypochlorite (0.28 g, 4% solution) was added at pH8-9 (maintained by adding aqueous sodium bicarbonate solution). Thereaction mixture was stirred for 20 minutes at 0° C. The organic layerwas separated and the aqueous layer was extracted with dichloromethane.The combined organic layers were washed with saturated aqueous sodiumbicarbonate solution, water, and brine. The organic layer was dried overanhydrous sodium sulphate, filtered, and concentrated under reducedpressure to afford the title compound (0.55 g).

Step f: Synthesis of3-[(2R,3S)-2-{[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]carbonyl}-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentyl]-1,2,3-benzotriazin-4(3H)-one

In a flame-dried flask,3-{3-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one(0.25 g) was taken up in dichloromethane (10 mL) and cooled to 0° C.Titanium tetrachloride (0.76 mL, 1 M solution) was added drop-wise andthe reaction mixture was stirred for 10 to 15 minutes. (−)-Sparteine(0.36 mL) was added slowly to the reaction mixture and stirred at 0° C.for 20 minutes. A solution of the compound obtained from step e above(0.17 g) in dichloromethane (10 mL) was added slowly, and stirring wascontinued at 0° C. After 3 hours, the reaction was quenched with thedrop-wise addition of saturated ammonium chloride solution, anddichloromethane was added. The organic layer was separated and theaqueous layer was extracted with dichloromethane. The organic layer waswashed with brine, dried over anhydrous sodium sulphate, andconcentrated under reduced pressure. The crude product thus obtained waspurified by silica gel flash column chromatography using 30% ethylacetate in hexane as eluant to afford the title compound (0.2 g).

Step g: Synthesis of(2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoicacid

To a stirred solution of the compound obtained from step f above (0.18g) in tetrahydrofuran:water (3:1, 10 mL), aqueous hydrogen peroxidesolution (30%, 0.15 mL) was added at 0° C., followed by the addition oflithium hydroxide monohydrate (17.6 mg) in water (2 mL). The reactionmixture was stirred at 0° C. until the completion of the hydrolysis. Thereaction mixture was concentrated and the residue was extracted withethyl acetate. The aqueous layer was acidified with sodium hydrogensulphate and extracted with ethyl acetate. The combined layers werewashed with water and brine, and dried over anhydrous sodium sulphate.The solvents were evaporated under reduced pressure and the cruderesidue was purified by silica gel flash column chromatography using 10%methanol in dichloromethane as eluant to afford the title compound(0.075 g).

Mass (m/z): 448.07 (M⁺+1);

¹HNMR (CD₃OD): δ 8.25-8.8.30 (d, 1H, J=8 Hz), 8.15-8.12 (d, 1H, J=8 Hz),8.05-8.00 (t, 1H, J=8 Hz), 7.89-7.85 (t, 1H, J=8 Hz), 7.58-7.55 (m, 1H),7.47-7.45 (d, 1H, J=8 Hz), 7.28-7.26 (d, 1H, J=8 Hz), 7.89-7.87 (m, 1H),7.61 (m, 2H), 7.53-7.59 (m, 1H), 7.30-7.25 (d, 2H J=8 Hz), 7.15-7.11 (t,2H, J=8 Hz), 4.81-4.79 (m, 2H), 3.92 (s, 1H), 3.22-3.16 (m, 1H),2.92-2.90 (m, 1H), 2.75-2.73 (m, 1H), 1.93-1.87 (m, 2H).

The following compounds were prepared employing procedures as providedin Examples 1 to 7C described above.

Compound Nos. 1 to 81, 86-88, 90-95, 97-119, 121-142, 144-203, 211-213,and 226-232 were prepared following Example 1; Compound Nos. 82-83 wereprepared following Example 2; Compound Nos 84-85 and 204 were preparedfollowing Example 3; Compound Nos. 89 and 96 were prepared followingExample 4; Compound Nos. 120 and 205-207 were prepared following Example5; Compound Nos. 143 and 208 were prepared following Example 6; andCompound Nos. 86, 209-210, and 214-225 were prepared following Example7.

Specific compounds, suitable for use, prepared in the present invention,are listed below:

-   (2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4-pyrimidin-5-ylphenyl)pentanoic    acid (Compound No. 1);

Mass (m/z): 446.0 (M⁺+1).

-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 2)

Mass (m/z): 531.09 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 3)

Mass (m/z): 458.82 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 4);-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 5)

Mass (m/z): 479.70 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 6)

Mass (m/z): 458.94 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 7)

Mass (m/z): 472.87 (M⁺+1);

-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 8);-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 9)

Mass (m/z): 461.87 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 10)

Mass (m/z): 473.79 (M⁺+1);

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 11)

Mass (m/z): 493.81 (M⁺+1);

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 12)

Mass (m/z): 479.77 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 13)

Mass (m/z): 473.86 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 14)

Mass (m/z): 510.66 (M⁺−18);

-   (2S,3R)-5-(4′-chloro-3′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 15)

Mass (m/z): 496.10 (M⁺+1);

-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 16)

Mass (m/z): 536.11 (M⁺+1);

-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 17)

Mass (m/z): 530.09 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 18)

Mass (m/z): 512.04 (M⁺+1);

-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 19)

Mass (m/z): 518.14 (M⁺+1);

-   (2S,3R)-2-[2-(5-tert-butyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-chlorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 20)

Mass (m/z): 534.09 (M⁺);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 21)

Mass (m/z): 512.08 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 22)

Mass (m/z): 458.14 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 23)

Mass (m/z): 492.07 (M⁺+1).

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 24)

Mass (m/z): 489.11 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 25)

Mass (m/z): 458.14 (M⁺+1);

-   (2S,3R)-5-(4′-ethylbiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 26)

Mass (m/z): 472.15 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]pentanoic    acid (Compound No. 27)

Mass (m/z): 492.08 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 28)

Mass (m/z): 478.09 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-pyrimidin-5-ylphenyl)pentanoic    acid (Compound No. 29)

Mass (m/z): 446.12 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 30)

Mass (m/z): 448.25 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4-pyridin-3-ylphenyl)pentanoic    acid (Compound No. 31)

Mass (m/z): 445.23 (M⁺+1);

-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 32)

Mass (m/z): 502.19 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 33)

Mass (m/z): 489.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 34)

Mass (m/z): 473.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 35)

Mass (m/z): 448.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 36)

Mass (m/z): 505.0 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 37)

Mass (m/z): 509.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-{2-[7-(6-methoxypyridin-3-yl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl]ethyl}-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 38)

Mass (m/z): 582.0 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 39)

Mass (m/z): 511.0 (M⁺+1);

-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 40)

Mass (m/z): 493.3 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 41)

Mass (m/z): 489.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-{2-[5-(6-methoxypyridin-3-yl)-4-oxo-1,2,3-benzotriazin-3(4H)-yl]ethyl}-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 42)

Mass (m/z): 582.0 (M⁺+1);

-   (2S,3R)-5-(4′-chloro-3′-fluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 43)

Mass (m/z): 519.0 (M⁺+23);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 44)

Mass (m/z): 490.0 (M⁺+1);

-   (2S,3R)-5-biphenyl-4-yl-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 45)

Mass (m/z): 444.0 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 46)

Mass (m/z): 476.0 (M⁺+1);

-   (2S,3R)-5-(3,3′-difluoro-4′-methoxybiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 47)

Mass (m/z): 510.0 (M⁺+1);

-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 48)

Mass (m/z): 502.0 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(1H-tetrazol-1-yl)phenyl]pentanoic    acid (Compound No. 49)

Mass (m/z): 458.0 (M⁺+23);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 50)

Mass (m/z): 493.0 (M⁺+1);

-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 51)

Mass (m/z): 498.0 (M⁺+23);

-   (2S,3R)-3-hydroxy-5-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 52)

Mass (m/z): 490.0 (M⁺+1);

-   (2S,3R)-5-biphenyl-4-yl-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 53)

Mass (m/z): 444.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 54)

Mass (m/z): 489.34 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-(3-fluoro-4-methoxyphenyl)pyridin-3-yl]-3-hydroxypentanoic    acid (Compound No. 55)

Mass (m/z): 493.16 (M⁺+1);

-   (2S,3R)-5-(4′-chloro-3-fluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 56)

Mass (m/z): 496.13 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[6-(4-methoxyphenyl)pyridin-3-yl]pentanoic    acid (Compound No. 57)

Mass (m/z): 475.13 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 58)

Mass (m/z): 492.13 (M⁺+1);

-   (2S,3R)-5-[6-(4-chlorophenyl)pyridin-3-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 59)

Mass (m/z): 479.12 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 60)

Mass (m/z): 476.16 (M⁺+1);

-   (2S,3R)-5-[4-(4-chlorophenyl)-2-thienyl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 61)

Mass (m/z): 484.0 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)-2-thienyl]pentanoic    acid (Compound No. 62)

Mass (m/z): 481.0 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-{4-[4-(trifluoromethyl)phenyl]-2-thienyl}pentanoic    acid (Compound No. 63)

Mass (m/z): 518.0 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[4-(3-fluoro-4-methoxyphenyl)-2-thienyl]-3-hydroxypentanoic    acid (Compound No. 64)

Mass (m/z): 498.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 65)

Mass (m/z): 526.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 66)

Mass (m/z): 526.0 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 67)

Mass (m/z): 492.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 68)

Mass (m/z): 542.29 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 69)

Mass (m/z): 548.54 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[2-fluoro-5-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 70)

Mass (m/z): 493.30 (M⁺+1);

-   (2S,3R)-5-(4′-chloro-4-fluorobiphenyl-3-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 71)

Mass (m/z): 495.72 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-fluoro-4′-(trifluoromethyl)biphenyl-3-yl]-3-hydroxypentanoic    acid (Compound No. 72)

Mass (m/z): 530.13 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[4-fluoro-3-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 73)

Mass (m/z): 493.37 (M⁺+1);

-   (2S,3R)-5-(4′-chloro-6-fluorobiphenyl-3-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 74)

Mass (m/z): 496.26 (M⁺+1);

-   (2S,3R)-5-(3′,6-difluoro-4′-methoxybiphenyl-3-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 75)

Mass (m/z): 509.77 (M⁺+1);

-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 76)

Mass (m/z): 492.56 (M⁺+1);

-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 77)

Mass (m/z): 480.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 78)

Mass (m/z): 462.19 (M⁺+1);

-   (2S,3R)-2-[2-(5-chloro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 79)

Mass (m/z): 546.32 (M⁺+1);

-   (2S,3R)-2-[2-(4-fluoro-1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 80)

Mass (m/z): 529.25 (M⁺+1);

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 81)

Mass (m/z): 498.27 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-phenylpentanoic    acid (Compound No. 82)

Mass (m/z): 368.0 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-phenylpentanoic    acid (Compound No. 83)

Mass (m/z): 368.07 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4(trifluoromethyl)phenyl]pentanoic    acid (Compound No. 84)

Mass (m/z): 458.0 (M⁺+23);

-   (2S,3R)-5-(4-tert-butylphenyl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 85)

Mass (m/z): 424.0 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 86)

Mass (m/z): 474.87 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 87)

Mass (m/z): 478.09 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 88)

Mass (m/z): 474.88 (M⁺+1);

-   (2R,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 89)

Mass (m/z): 478.2 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 90)

Mass (m/z): 462.32 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 91)

Mass (m/z): 478.38 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 92)

Mass (m/z): 514.20 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 93)

Mass (m/z): 508.29 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 94);-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 95)

Mass (m/z): 493.37 (M⁺+1);

-   (2R,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 96)

Mass (m/z): 474.87 (M⁺+1);

-   (2S,3R)-5-(2′,4′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 97)

Mass (m/z): 480.13 (M⁺+1);

-   (2S,3R)-2-[2-(6-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 98)

Mass (m/z): 482.15 (M⁺+1);

-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 99)

Mass (m/z): 482.15 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-(4′-isopropylbiphenyl-4-yl)pentanoic    acid (Compound No. 100)

Mass (m/z): 486.18 (M⁺+1);

-   (2S,3R)-5-(3′-chloro-4′-fluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 101)

Mass (m/z): 496.12 (M⁺+1);

-   (2S,3R)-5-(4′-butylbiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 102)

Mass (m/z): 500.42 (M⁺+1);

-   (2S,3R)-5-(2′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 103)

Mass (m/z): 462.32 (M⁺+1);

-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 104)

Mass (m/z): 466.31 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 105)

Mass (m/z): 462.38 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 106)

Mass (m/z): 513.35 (M⁺+1);

-   (2S,3R)-5-[6-(3,4-difluorophenyl)pyridin-3-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 107)

Mass (m/z): 481.32 (M⁺+1);

-   (2S,3R)-5-[6-(4-chloro-3-fluorophenyl)pyridin-3-yl]-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 108)

Mass (m/z): 497.30 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-(4-fluorophenyl)pyridin-3-yl]-3-hydroxypentanoic    acid (Compound No. 109)

Mass (m/z): 463.35 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-[6-(3-fluoro-4-methylphenyl)pyridin-3-yl]-3-hydroxypentanoic    acid (Compound No. 110)

Mass (m/z): 477.34 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 111)

Mass (m/z): 482.38 (M⁺+1);

-   (2S,3R)-2-[2-(8-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 112);-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]pentanoic    acid (Compound No. 113)

Mass (m/z): 484.39 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 114)

Mass (m/z): 542.36 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 115)

Mass (m/z): 472.12 (M⁺+1);

-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 116)

Mass (m/z): 476.23 (M⁺+1).

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 117)

Mass (m/z): 494.24 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 118)

Mass (m/z): 473.38 (M⁺+1);

-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 119)

Mass (m/z): 516.28 (M⁺+1);

-   (2R,3S)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 120)

Mass (m/z): 474.87 (M⁺+1);

-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 121)

Mass (m/z): 510.23 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 122)

Mass (m/z): 510.23 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 123)

Mass (m/z): 512.31 (M⁺+1);

-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 124)

Mass (m/z): 490.30 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(1-isobutyl-1H-pyrazol-4-yl)phenyl]-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 125)

Mass (m/z): 504.33 (M⁺+1);

-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoic    acid (Compound No. 126)

Mass (m/z): 510.23 (M⁺+1);

-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 127)

Mass (m/z): 492.26 (M⁺+1).

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 128)

Mass (m/z): 510.30 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 129)

Mass (m/z): 504.38 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 130)

Mass (m/z): 547.29 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 131)

Mass (m/z): 549.30 (M⁺+1);

-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 132)

Mass (m/z): 547.29 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 133)

Mass (m/z): 527.40 (M⁺+1);

-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoic    acid (Compound No. 134)

Mass (m/z): 531.36 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 135)

Mass (m/z): 488.34 (M⁺+1);

-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 136)

Mass (m/z): 494.33 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 137)

Mass (m/z): 494.33 (M⁺+1);

-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 138)

Mass (m/z): 476.30 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 139)

Mass (m/z): 496.30 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 140)

Mass (m/z): 476.35 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 141);-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 142)

Mass (m/z): 490.34 (M⁺+1);

-   (2S,3S)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 143)

Mass (m/z): 475.21 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 144)

Mass (m/z): 512.32 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 145)

Mass (m/z): 514.37 (M⁺+1);

-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 146)

Mass (m/z): 506.38 (M⁺+1);

-   (2S,3R)-5-[4-(2,3-dihydro-1,4-benzodioxin-6-yl)phenyl]-3-hydroxy-2-[2-(8-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 147)

Mass (m/z): 532.38 (M⁺+1);

-   (2S,3R)-5-[4-(6-chloropyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 148)

Mass (m/z): 479.36 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 149)

Mass (m/z): 542.11 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 150)

Mass (m/z): 542.11 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-(4′-methylbiphenyl-4-yl)pentanoic    acid (Compound No. 151)

Mass (m/z): 488.09 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 152)

Mass (m/z): 504.06 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 153)

Mass (m/z): 493.01 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 154)

Mass (m/z): 523.02 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 155)

Mass (m/z): 511.04 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 156)

Mass (m/z): 507.05 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 157)

Mass (m/z): 507.05 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 158)

Mass (m/z): 504.09 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 159)

Mass (m/z): 508.03 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 160)

Mass (m/z): 505.11 (M⁺+1);

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 161)

Mass (m/z): 510.04 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 162)

Mass (m/z): 505.11 (M⁺+1);

-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 163)

Mass (m/z): 526.95 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 164)

Mass (m/z): 529.00 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 165)

Mass (m/z): 507.03 (M⁺+1);

-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 166)

Mass (m/z): 476.01 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 167)

Mass (m/z): 489.05 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 168)

Mass (m/z): 488.06 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 169)

Mass (m/z): 472.03 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(5-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 170)

Mass (m/z): 491.98 (M⁺+1);

-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 171)

Mass (m/z): 492.00 (M⁺+1);

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 172)

Mass (m/z): 509.98 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 173)

Mass (m/z): 557.99 (M⁺+1);

-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 174)

Mass (m/z): 506.04 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 175)

Mass (m/z): 526.91 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)-2-thienyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 176);-   (2S,3R)-5-[2-fluoro-4-(6-methoxypyridin-3-yl)phenyl]-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 177)

Mass (m/z): 523.01 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 178);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(6-methylpyridin-3-yl)phenyl]pentanoic    acid (Compound No. 179)

Mass (m/z): 489.07 (M⁺+1);

-   (2S,3R)-5-[4-(2-chloropyridin-3-yl)phenyl]-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 180)

Mass (m/z): 508.99 (M⁺+1);

-   (2S,3R)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 181)

Mass (m/z): 493.19 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 182)

Mass (m/z): 496.17 (M⁺+1);

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 183)

Mass (m/z): 498.15 (M⁺+1);

-   (2S,3R)-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)pentanoic    acid (Compound No. 184)

Mass (m/z): 492.16 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(2-methoxypyrimidin-5-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 185)

Mass (m/z): 476.13 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 186)

Mass (m/z): 480.08 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 187)

Mass (m/z): 480.15 (M⁺+1);

-   (2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxypentanoic    acid (Cmpound No. 188)

Mass (m/z): 500.07 (M⁺+1);

-   (2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 189)

Mass (m/z): 500.13 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 190)

Mass (m/z): 484.15 (M⁺+1);

-   (2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxypentanoic    acid (Compound No. 191)

Mass (m/z): 502.16 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-2-[2-(6-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 192;

Mass (m/z): 507.22 (M⁺+23);

-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 193);-   (2S,3R)-3-hydroxy-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-[4-(2-methoxypyrimidin-5-yl)phenyl]pentanoic    acid (Compound No. 194)

Mass (m/z): 506.12 (M⁺+1);

-   (2S,3R)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxy-5-[4-(2-methoxypyrimidin-5-yl)phenyl]pentanoic    acid (Compound No. 195)

Mass (m/z): 476.18 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(1-oxophthalazin-2(1H)-yl)ethyl]pentanoic    acid (Compound No. 196)

Mass (m/z): 465.26 (M⁺+1);

-   (2S,3R)-5-[2-fluoro-4-(1-methyl-1H-pyrazol-4-yl)phenyl]-3-hydroxy-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1    (2H)-yl)ethyl]pentanoic acid (Compound No. 197)

Mass (m/z): 445.25 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-{2-[4-oxo-7-(trifluoromethyl)-1,2,3-benzotriazin-3(4H)-yl]ethyl}pentanoic    acid (Compound No. 198)

Mass (m/z): 543.22 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(1-oxophthalazin-2(1H)-yl)ethyl]pentanoic    acid (Compound No. 199)

Mass (m/z): 474.25 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(3-methyl-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl)ethyl]pentanoic    acid (Compound No. 200)

Mass (m/z): 454.24 (M⁺+1);

-   (2S,3R)-2-[2-(7,9-dioxo-8-azaspiro[4.5]dec-8-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 201)

Mass (m/z): 495.27 (M⁺+1);

-   (2S,3R)-2-[2-(2,4-dioxo-2H-1,3-benzoxazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 202)

Mass (m/z): 491.17 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(3,4,4-trimethyl-2,5-dioxoimidazolidin-1-yl)ethyl]pentanoic    acid (Compound No. 203)

Mass (m/z): 470.12 (M⁺+1);

-   (2S,3R)-5-(4-chloro-3-fluorophenyl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 204)

Mass (m/z): 420.06 (M⁺+1);

-   (2R,3S)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 205)

Mass (m/z): 476.07 (M⁺+1);

-   (2R,3S)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-5-(4′-fluorobiphenyl-4-yl)-3-hydroxypentanoic    acid (Compound No. 206)

Mass (m/z): 462.03 (M⁺+1);

-   (2R,3S)-5-(3′,4′-difluorobiphenyl-4-yl)-2-[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 207)

Mass (m/z): 480.03 (M⁺+1);

-   (2S,3S)-3-hydroxy-5-(4′-methoxybiphenyl-4-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 208)

Mass (m/z): 474.31 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(5-methylpyridin-2-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 209)

Mass (m/z): 459.21 (M⁺+1);

-   (2S,3R)-5-[4-(6-fluoropyridin-3-yl)phenyl]-3-hydroxy-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 210)

Mass (m/z): 463.17 (M⁺+1);

-   (2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 211)

Mass (m/z): 530.33 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 212)

Mass (m/z): 492.29 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 213)

Mass (m/z): 490.34 (M⁺+1);

-   (2S,3R)-5-(3′-fluoro-4′-methylbiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 214);-   (2S,3R)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-5-[4′-(trifluoromethyl)biphenyl-4-yl]pentanoic    acid (Compound No. 215)

Mass (m/z): 498.09 (M⁺+1);

-   (2S,3R)-5-(2′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 216)

Mass (m/z): 466.06 (M⁺+1);

-   (2S,3R)-5-(4′-fluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 217)

Mass (m/z): 448.07 (M⁺+1);

-   (2S,3R)-5-(3′-fluoro-4′-methoxybiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 218)

Mass (m/z): 478.22 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(2-methoxypyrimidin-5-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 219)

Mass (m/z): 462.23 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 220)

Mass (m/z): 461.23 (M⁺+1)

-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 221)

Mass (m/z): 444.24 (M⁺+1);

-   (2S,3R)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]-5-[4′-(trifluoromethoxy)biphenyl-4-yl]pentanoic    acid (Compound No. 222)

Mass (m/z): 514.14 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-methylpyridin-3-yl)phenyl]-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 223)

Mass (m/z): 445.18 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 224)

Mass (m/z): 464.18 (M⁺+1);

-   (2S,3R)-5-(3′,4′-difluorobiphenyl-4-yl)-3-hydroxy-2-[(4-oxo-1,2,3-benzotriazin-3(4H)-yl)methyl]pentanoic    acid (Compound No. 225)

Mass (m/z): 466.20 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-[4-(6-hydroxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 226)

Mass (m/z): 461.23 (M⁺+1);

-   (2S,3R)-3-hydroxy-5-(4′-methylbiphenyl-4-yl)-2-{2-[4-oxo-7-(trifluoromethyl)-1,2,3-benzotriazin-3(4H)-yl]ethyl}pentanoic    acid (Compound No. 227)

Mass (m/z): 526.16 (M⁺+1);

-   (2S,3R)-2-[2-(2,4-dioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 228)

Mass (m/z): 490.17 (M⁺+1);

-   (2S,3R)-3-(acetyloxy)-5-[4-(6-methoxypyridin-3-yl)phenyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoic    acid (Compound No. 229)

Mass (m/z): 517.06 (M⁺+1);

-   (2S,3R)-2-[2-(8-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-[4-(6-methoxypyridin-3-yl)phenyl]pentanoic    acid (Compound No. 230)

Mass (m/z): 509.17 (M⁺+1);

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-2-[2-(2,4-dioxo-2H-1,3-benzoxazin-3(4H)-yl)ethyl]-3-hydroxypentanoic    acid (Compound No. 231)

Mass (m/z): 493.93 (M⁺+1); and

-   (2S,3R)-5-(4′-chlorobiphenyl-4-yl)-3-hydroxy-2-(2-{[(2-hydroxyphenyl)    carbonyl]amino}ethyl)pentanoic acid (Compound No. 232)

Mass (m/z): 468.14 (M⁺+1).

Example Assay for Matrix Metalloproteinases (MMPs)

New chemical entities of the present invention and correspondingstandards used in the present invention were prepared (stock 10 mM) in100% DMSO and subsequent dilutions were made in 50% DMSO-50% TCNB (50 mMTris, 10 mM CaCl₂, 150 mM NaCl, 0.05% Brij-35, pH 7.5). 1 μl of thecompound and 88 μl of TCNB was added to the wells of a 96 well plate toachieve the desired final concentration of NCE (final DMSO concentrationshould not exceed 0.5%). 1 μl of activated, recombinant MMPs was addedto each well (20-100 mg/100 μl reaction mixture) except the “negativewell”. (MMP-1, 9, and 14 enzymes require prior activation. For this, thesupplied enzyme was incubated with either APMA, final concentration 1mM, for a time period of 1 hour at 37° C.). Incubation was done at roomtemperature for 4 to 5 minutes. Reaction was initiated with 10 μl of 100μM substrate (ES001: Aliquots were freshly diluted in TCNB; stock: 2 mM)and increase in florescence was monitored at excitation wavelength 320nm followed by emission at 405 nm for 25 to 30 cycles. Increase inflorescence (RFU) was calculated for positive, negative, andNCE/standard wells. The percent inhibition compared to controls wascalculated and IC₅₀ values were determined using Graph-prism software.

The present invention relates to compounds that act as dual MMP-9/12inhibitors, which have desirable activity profiles and beneficialpotency, selectivity, and/or pharmacokinetic properties.

In particular, compounds disclosed herein exhibited activity in MMP-9assays from ≦0.02 nM to about 40 μM, or from ≦0.02 nM to about 200 nM,or from ≦0.02 nM to about 20 nM, or from ≦0.02 nM to about 1.0 nM, orfrom ≦0.02 nM to about 0.3 nM. Compounds disclosed herein exhibitedactivity in MMP-12 assays from ≦0.02 nM to about 3.8 μM, or from ≦0.02nM to about 200 nM, or from ≦0.02 nM to about 20 nM, or from ≦0.02 nM toabout 1.0 nM, or from ≦0.02 nM to about 0.3 nM. Particular compoundstested (Nos. 2-28, 30, 32-43, 46, 50-51, 55-58, 60-61, 63, 65-69, 76,79-80, 86-89, 93-96, 98, 106-107, 113-122, 126, 130-132, 134, 136-138,143-144, 148-150, 155, 157, 159, 173-175, 177, 179, 181-182, 184-186,190, 192-195, 198, and 210-211) exhibited activity in MMP-1 assays fromabout 100 nM to about 10 μM, for example, from about 100 nM to about 5μM, or from about 100 nM to about 2 μM, or from about 100 nM to about1.04 indicating that compounds of the present invention can be selectiveover MMP-1 by ≧100 fold.

Assay for In Vivo LPS Induced Rat Neutrophilia Model

Male wistar rats were treated with vehicle/NCEs (new chemical entities)or standard drug and 2 hours later challenged with lipopolysaccharide(LPS) in phosphate buffered saline (PBS), by oro-intra tracheal route(400 μL of 50 μg/mL). Negative control animals received PBS alone.Intratracheal instillation was done under ketamine and xylazineanaesthesia. Two hours post-LPS challenge, the rats were euthanised andbronchoalveolar lavage (BAL) was performed. The TLC, DLC was done toenumerate neutrophil count in the BAL fluid and results were expressedas percent inhibition using the following formula

$\frac{{NeuLPS} - {NeuTEST}}{{NeuLPS} - {NeuPBS}} \times 100$Where,NeuLPS=Neutrophil count in vehicle-treated LPS challenged groupNeuTEST=Neutrophil count in group treated with a given dose of testcompoundNeuPBS=Neutrophil in vehicle-treated group challenged with PBSSolubility AssessmentEquilibrium Solubility:

The pH-solubility profile of a compound is determined at 37° C. inaqueous media with a pH in the range of 1-7.5. A sufficient number of pHconditions are evaluated to accurately define the pH-solubility profile.Standard buffer solutions described in the USP are consideredappropriate for use in solubility studies.

The compound is weighed and transferred to the flasks. Media are addedto each conical flask, and the flask is sealed with a stopper andparaffin film. The volume added is dependant upon the volume requiredfor analysis of the content of the compound. The pH of the solution ismeasured after addition of the compound. The flask is observedintermittently. If the drug substance is completely dissolved,additional amounts of the compound are added until saturation(undissolved residue) is observed and the pH is measured. Flasks areremoved from the water bath after equilibrium is achieved. The saturatedsolution is filtered through 0.45 μm membrane filter and the samples areanalyzed to estimate the content of the test compound.

Pharmacokinetic Screening Assays for Matrix Metalloproteinase (MMP 9/12)Inhibitors

Intrinsic Clearance:

Intrinsic clearance (or metabolism stability) is assessed by estimatingthe rate of initial decay of the parent compound in a suitablebiological matrix, like human liver microsomes.

The study reaction consists of NADPH regeneration system and livermicrosomes of the various species of interest (human, rat, dog, mouse)added into buffer at a concentration of 0.5 mg/mL. After a shortpreincubation, the metabolic reaction is initiated by the addition of 5μL of the substrate stock (100 μM) to yield a final concentration of 0.5μM in the reaction. Periodic aliquots are drawn every three minutes for30 minutes, quenched, and the test compound concentration is estimatedby LCMS. The rate of disappearance is estimated as the first order slopeof the % of parent remaining vs. time graph. The rate of decay isnormalized to the unit concentration of the test compound and proteinand extrapolated to 1 g of liver by using scaling factors (52.5 mg ofCYP microsomal protein per gram of liver).

In Vitro Glucuronidation:

A comparative assay in the form of intrinsic clearance (see above) withthe addition of glucuronic acid and alamethacin to compare primarily theparent disappearance due to glucuronidation. Expressed as rate ofclearance and normalized to per gram of liver.

Plasma Protein Binding:

Assessment by the equilibrium dialysis method where the unbound compounddiffuses across a semi-permeable membrane and equilibrates withphosphate buffer (pH 7.4) is estimated, and is subtracted from the totaldrug in plasma to determine the percentage bound.

Equilibrium dialysis membranes are soaked overnight and the assembly isprepared. The test drug is spiked into plasma (100 and 1000 ng/mL) andincubated at 37° C. and is transferred into the equilibrium apparatuswith plasma added in one compartment and buffer added in the other. Theunit is rotated at constant rpm at 37° C. for four hours to allow theunbound compound to dialyse and distribute within the buffer chamber.After four hours the plasma and the buffer are removed from therespective compartments and the test compound concentrations areestimated. The percentage bound is estimated from the test compoundconcentrations.

Alternate methods include the ultra filtration method where the compoundspiked in plasma (100 and 1000 ng/mL) is filtered with Centricon®filters having molecular weight cut off of 30,000 DA to prepare theretentate and ultra filtrate. The test compound is estimated in both andthe percentage bound is calculated.

We claim:
 1. A compound which is selected from:(2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoicacid (Compound No. 121);(2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoicacid (Compound No. 122);(2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoicacid (Compound No. 123);(2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)pentanoicacid (Compound No. 126);(2S,3R)-2-[2-(7-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoicacid (Compound No. 130);(2S,3R)-2-[2-(6,7-difluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoicacid (Compound No. 131);(2S,3R)-2-[2-(5-chloro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoicacid (Compound No. 132);(2S,3R)-3-hydroxy-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoicacid (Compound No. 133);(2S,3R)-2-[2-(5-fluoro-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]-3-hydroxy-5-{6-[4-(trifluoromethyl)phenyl]pyridin-3-yl}pentanoicacid (Compound No. 134);(2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 140);(2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(6-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 141);(2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(7-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 142);(2S,3R)-3-hydroxy-5-[4-(1-methyl-1H-pyrazol-4-yl)-2-thienyl]-2-[2-(4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 176);(2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(6-methoxy-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 178); and(2S,3R)-3-hydroxy-5-(6′-methoxy-2,3′-bipyridin-5-yl)-2-[2-(8-methyl-4-oxo-1,2,3-benzotriazin-3(4H)-yl)ethyl]pentanoicacid (Compound No. 213).
 2. A pharmaceutical composition comprising atherapeutically effective amount of a compound of claim 1, together withpharmaceutically acceptable carriers, excipients, or diluents.
 3. Thepharmaceutical composition of claim 2 further comprising one or moreadditional active ingredients selected from the group consisting of: a.Anti-inflammatory agents, selected from (i) the nonsteroidalanti-inflammatory agents piroxicam, diclofenac, propionic acids,fenamates, pyrazolones, salicylates, PDE-4/p38 MAP Kinase/Cathepsininhibitors, CCR-3 antagonists, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists, cell adhesion inhibitors, andadenosine 2a agonists; (ii) leukotrienes LTC4/LTD4/LTE4/LTB4-Inhibitors,5-lipoxygenase inhibitors, and PAF-receptor antagonists; (iii) Cox-2inhibitors; (iv) other MMP inhibitors; (v) interleukin-1 inhibitors;(vi) the corticosteroids alclometasone, amcinonide, amelometasone,beclometasone, betamethasone, budesonide, ciclesonide, clobetasol,cloticasone, cyclomethasone, deflazacort, deprodone, dexbudesonide,diflorasone, difluprednate, fluticasone, flunisolide, halometasone,halopredone, hydrocortisone, methylprednisolone, mometasone,prednicarbate, prednisolone, rimexolone, tixocortol, triamcinolone,ulobetasol, rofleponide, GW 215864, KSR 592, ST-126, dexamethasone, andpharmaceutically acceptable salts or solvates thereof; b) Beta-agonists,selected from β2-agonists albuterol, salbutamol, biltolterol,pirbuterol, levosalbutamol, tulobuterol, terbutaline, bambuterol,metaproterenol, fenoterol, salmeterol, carmoterol, arformoterol,formoterol, and pharmaceutically acceptable salts or solvates thereof;c) antihypertensive agents selected from (i) ACE inhibitors enalapril,lisinopril, valsartan, Telmisartan, and quinapril; (ii) angiotensin IIreceptor antagonists and agonists losartan, candesartan, irbesartan,valsartan, and eprosartan; (iii) β-blockers; and (iv) calcium channelblockers; d) immunosuppressive agents selected from cyclosporine,azathioprine, and methotrexate; anti-inflammatory corticosteroids; ande) antiinfective agents consisting of antibiotics and antiviral.